H e red i t a r y B re a s t

and Ovarian Cancer

( H B O C ) : Cl i n i c a l
F e a t u re s a n d
C o u n s e l i n g fo r B R C A 1
a n d B R C A 2 , Ly n c h
S y n d ro m e , C o w d e n
S y n d ro m e , a n d
L i - F r a u m e n i S y n d ro m e
a,b,c,d,e,f,
Lee P. Shulman, MD *

KEYWORDS
 Hereditary breast cancer  Hereditary ovarian cancer
 BRCA1/2  Genetic counseling  Lynch syndrome

Recent committee opinions from the Society of Gynecologic Oncologists1 and The
American College of Obstetricians and Gynecologists2 highlight the need for cancer
risk assessment to be a process in which genetic counseling plays a seminal role. It
is the role of the genetic counselor to obtain relevant information concerning an individ-
ual’s risk, to explain the process to the patient, explain how family history and laboratory
testing provide an adjusted risk for developing cancer, and finally, to provide a lucid

This work is supported in part by the generosity of the Bears’ Care Foundation.
a
Division of Clinical Genetics, Feinberg School of Medicine of Northwestern University,
Chicago, IL, USA
b
Northwestern Ovarian Cancer Early Detection and Prevention Program, Feinberg School of
Medicine of Northwestern University, Chicago, IL, USA
c
Department of Obstetrics and Gynecology, Feinberg School of Medicine of Northwestern
University, Chicago, IL, USA
d
Cancer Genetics Program, Feinberg School of Medicine of Northwestern University, Chicago,
IL, USA
e
Robert H. Lurie Comprehensive Cancer Program, Feinberg School of Medicine of North-
western University, Chicago, IL, USA
f
University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA
* Prentice Women’s Hospital, 250 East, Superior Street, Room 05-2174, Chicago, IL 60611.
E-mail address: [email protected]

Obstet Gynecol Clin N Am 37 (2010) 109–133

doi:10.1016/j.ogc.2010.03.003 obgyn.theclinics.com
0889-8545/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
110 Shulman

explanation of the risk for cancer development along with the preventative, screening,
and diagnostic processes that are available to the patient based on the adjusted risk. It
is indeed a complex and challenging task, given the emotional and psychosocial factors
that affect the entire process and that must be addressed by the counselor.
The development and implementation of genetic counseling has been, until
recently, mostly geared to pediatric, infertility, and prenatal issues. Counseling was
initially based on mathematical algorithms (Bayesian analysis) that calculated the like-
lihood that a child or fetus would be affected; no specific prenatal testing was available
and in many situations, the eventual pediatric diagnosis was based on phenotypic
presentation or crude analyte measurement rather than a molecular assay. As such,
disparate conditions with similar phenotypic presentations were classified as being
manifestations of a similar disorder, eventually leading to inaccurate evaluations
and counseling. While an important element of counseling was and remains emotional
support for the patient, in many cases this was all that could be offered to those who
had had an adverse perinatal or pediatric outcome, and were seeking reassurance
and accurate evaluations for future children and other family members.
As understanding of the pathophysiology of diseases and disorders improved,
genetic counseling began to provide more detailed and accurate assessment of the
risk for particular conditions in future pregnancies and children. However, it was the
development of ultrasound and amniocentesis that allowed for prenatal diagnosis,
and thus more accurate counseling, to be provided to prospective parents. This further
expanded with the delineation of the molecular basis for certain genetic disorders such
as sickle cell disease and cystic fibrosis. Indeed, it was this step that laid the foundation
for moving genetic counseling away from mathematical estimations of pediatric and
prenatal risk to a more accurate assessment of risk for an increasing number of
prenatal, pediatric, and adult conditions, thus changing the overall approach and use
of genetic counseling in the evolving evidence-based approach to health care.
We now arrive at the current role of genetic counseling, and in particular, cancer
genetic counseling. The completion of the Human Genome Project provided a virtual
dictionary of gene and DNA sequences, all serving as a template for determining which
sequences were associated with a variety of diseases as well as particular traits and
characteristics. One disease state that was likely to be highly amenable to not only this
new information but to the evolving and emerging technologies used to gather and
interpret this molecular information was cancer. This article provides an overview of
the molecular changes associated with inherited gynecologic malignancies and the
incorporation of this information in the counseling of individuals at increased risk for
developing malignancies, as well as conventional and emerging approaches to the
screening of the general population.
The author examines cancer genetic counseling and its role in women’s health care.
The focus is hereditary breast and ovarian cancer (HBOC); however, cancer predispo-
sition caused by genes other than BRCA1/2 is also considered. The aim is to provide
the reader with a foundation for counseling based on fundamental knowledge of the
genes and their clinical consequences. The reader is then guided through the
mechanics of risk assessment for individual patients, concluding with the psychoso-
cial implications of counseling.

THE GENES AND BIOLOGY

Tumor Suppressor Genes
Two separate and distinct tumor suppressor genes, BRCA1 and BRCA2, account for
the approximately 85% of all cases of hereditary breast and epithelial ovarian cancer
 Hereditary Breast and Ovarian Cancer 111

(EOC),3 although these 2 genes account for a smaller percentage of isolated familial
breast cancer cases in the absence of EOC.4 BRCA1 is located on chromosome
17q21, contains 22 coding exons, and spans 80 kb DNA, and BRCA2 is located on
chromosome 13q12-13, contains 26 coding exons, and spans 70 kb DNA. Both genes
are part of the DNA break repair pathway and appear to function as tumor suppressor
genes, with mutations resulting in a highly penetrant susceptibility to the development
of breast cancer and EOC. Mutations of BRCA1 and BRCA2 associated with the
development of both malignancies are found throughout the coding regions and at
splice sites, with most of these mutations being small insertions or deletions that
lead to frameshift mutations, nonsense mutations, or splice site alterations. All of these
genetic alterations invariably lead to premature protein termination and altered or
absent proteins that fail to suppress the development of malignancies in breast and
ovarian/epithelial tissues. In addition to these mutations and some missense muta-
tions, large deletions and rearrangements not detectable by standard polymerase
chain reaction (PCR) have recently been identified and are now part of the molecular
testing provided to those undergoing genetic testing for BRCA mutations. Palma and
colleagues5 reported that genomic rearrangements, detected by an analysis separate
from conventional gene sequencing and aimed at detecting large gene rearrange-
ments not amenable to detection by conventional analyses6 (eg, BART analysis [BRA-
CAnalysis Rearrangement Test]), accounted for 18% of BRCA1/2 mutations in
non-Ashkenazi Jewish probands with no such rearrangements being detected in
Ashkenazi Jewish probands.
The frequency of BRCA1 or BRCA2 mutations in the general population is estimated
to be 1 in 300 to 1 in 800,7 though a more recent study by Risch and colleagues8 in
Canada suggest that these frequencies may be considerably higher, at 1 in 140 to 1
in 300. However, some populations and communities have a higher frequency of
certain BRCA1/2 mutations than is found in the general population. In the United
States, BRCA1/2 mutations are found in approximately 1 of every 40 individuals of
Eastern European (Ashkenazi) Jewish ancestry. What also distinguishes this commu-
nity is that 3 mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2)
account for approximately 98% of mutations detected.9 In Iceland, the 999del5 muta-
tion in BRCA2 accounts for approximately 7% of all cases of EOC occurring in Ice-
landers.10 These mutations are known as ‘‘founder mutations,’’ so named because
in certain populations begun by a small ancestral group isolated by societal behavior
or geography, certain genes in the original ‘‘founders’’ of a community or population
can become far more common in succeeding generations after initiation of the isola-
tion than would occur in the general population. The identification of founder muta-
tions allows for more facile screening of individuals of those groups associated with
these mutations. As such, evaluating individuals of Eastern European Jewish ancestry
at increased risk for a BRCA1 or BRCA2 mutation based on family history is now
accomplished by first determining the presence of one of these 3 mutations unless
analysis of an affected relative shows that the BRCA1/2 mutation in the family is not
one of these 3 mutations. Evaluating for these 3 mutations in high-risk members of
the Ashkenazi Jewish community is not only easier than gene sequencing but also
less costly. However, even in some clinical scenarios in which a single putative
BRCA1/2 mutation is of interest in the risk assessment process, a ‘‘single site’’ anal-
ysis would potentially be augmented with a founder mutation analysis or even full gene
sequencing if the family history indicates that another mutation may be present,
possibly from the other parental lineage. For individuals from populations associated
with founder mutations who are at increased risk for BRCA1/2 mutations based on
family history and found not to have one of the founder mutations, gene sequencing
112 Shulman

and rearrangement analysis can be offered after a ‘‘negative’’ result to provide

a complete and thorough molecular evaluation.
Mismatch Repair Genes
Lynch syndrome (LS) is caused by gene mutations in the multistep mismatch repair
(MMR) system. MMR genes are located on 5 different chromosomes and encode
for proteins that recognize and repair damage in the DNA that leads to DNA
mismatches. One complex of proteins consisting of the protein MSH2 combined
with MSH6 or MSH3 recognizes the DNA mismatch and binds to the site. An inactivat-
ing mutation of MSH2 blocks the ability to recognize a DNA mismatch, negating the
function of this complex. Mutations of either MSH6 or MSH3, on the other hand,
may not have a similar deleterious effect as these 2 proteins have overlapping func-
tions, and thus an inactivating or adverse mutation in one may not adversely affect
the function of the overall MMR system. Once a mismatch is recognized, MLH1
(with PMS1 or PMS2) then provides the necessary steps to resynthesize the DNA
strand in its original and correct sequence.
A total of 7 MMR enzymes have been delineated, and mutations in each of the 7
genes have been identified (Table 1).11 Mutations in the MLH1 and MSH2 genes
make up approximately 90% of observed mutations in MMR genes and are followed
next by mutations in MSH6 and PMS2. Mutations in the remaining 3 genes are not
commonly observed in LS families. The type of MMR mutation provides important
information as to the risk for developing a particular malignancy in women with LS
mutations. While MLH1 and MSH2 gene mutations are the most common mutations
found in cases of colorectal cancer (CRC), Wijnen and colleagues12 found that women
carrying MSH6 mutations were twice as likely to develop endometrial cancer as
women who carried MSH2 or MLH1 mutations, and Watson and colleagues13
reported that the risk for EOC was significantly higher in families with MSH2 mutations
compared with families with MLH1 mutations.
It is interesting that the mechanism by which MMR gene mutations predispose to
tumor development appear to differ from the loss of heterozygosity observed in
HBOC. Aaltonen and colleagues14 found no loss of heterozygosity at a locus coin-
ciding with the MSH2 site on chromosome 2 linked to colorectal cancer in 14 cases
from 3 families, strongly suggestive of a molecular mechanism for LS different from
biallelic inactivation and alteration of tumor-suppressing gene function in cancer
susceptibility syndromes such as HBOC. Another explanation may be that MMR
mutations adversely affect the DNA mismatch repair mechanism without the loss of
heterozygosity, thus leading to a ‘‘domino-like’’ cascade on those cellular

Table 1
MMR genes associated with mismatch repair system

Gene Name Mutation Frequency in LS pts Chromosome Locus

MLH1 40%–45% 3p21.3
MSH2 40%–45% 2p22-p21
MSH6 7%–10% 2p16
PMS1 Unknown 2q31-q33
PMS2 <5% 7p22
MSH3 0 5q11-q12
MLH3 0 14q24.3
 Hereditary Breast and Ovarian Cancer 113

mechanisms responsible for the maintenance of proper cellular growth and develop-
ment, and thus predisposing those targeted cells and organs to malignant transforma-
tion with a mechanism different than that observed in HBOC. These inactivating
mutations not only prevent the repair of damaged DNA but also increase the rate of
mutations at the DNA microsatellites of growth-regulating genes. Microsatellites are
short (1–5 base pairs), polymorphic DNA sequences that are repeated 15 to 30 times
at a given locus and are distributed throughout the genome. Microsatellite instability
(MSI) thus serves as a marker for MMR mutations; indeed, microsatellite instability
analysis and immunohistochemical (IHC) staining for the presence or absence of the
proteins MLH1, MSH2, MSH6, and PMS2 serve as preliminary diagnostic steps in
determining the presence of a DNA repair defect for many individuals at increased
risk for MMR mutations. IHC can evaluate tumor tissue for gene expression but cannot
assess the functionality of any of these proteins. As such, IHC alone cannot determine
whether the protein present does not function properly because of a missense muta-
tion; accordingly, IHC should be combined with MSI to screen prospective tumors for
MMR mutations. MSI is a common feature of LS-associated tumors; however, studies
of MSI in ovarian tumor tissue from EOC have not provided consistent diagnostic
correlation.

CLINICAL FEATURES
Hereditary Breast and Ovarian Cancer
HBOC syndrome is one of the most common reasons for referral for genetic coun-
seling and consideration of genetic testing. HBOC is characterized by a strong family
history of breast cancer and EOC, with most such families having more cases of breast
cancer than ovarian cancer. HBOC families, like other families with hereditary cancer
predisposition syndromes, are characterized by a far earlier age of onset than is seen
in the general population, as well as a higher likelihood of bilateral disease. In addition,
HBOC families have a markedly higher frequency of family members with breast
cancer and EOC occurring in the same individual and, for some gene mutations,
a strikingly higher risk for breast cancer in men.
A study by Ramus and Gayther15 showed that 81% of families with at least 2 cases
of EOC and 1 case of breast cancer had a deleterious mutation in BRCA1 or BRCA2,
thus confirming earlier studies and models demonstrating that the majority of cases of
HBOC are associated with BRCA1/2 mutations.16,17 Indeed, Lynch and colleagues3
reported that BRCA1/2 mutations were found in approximately 6% to 8% of isolated
EOC cases, but in 80% to 90% of HBOC cases.
As BRCA1 and BRCA2 are autosomal genes with high penetrance, transmission
can occur either maternally or paternally; accordingly, equal attention must be paid
to the assessment of paternal relatives of an individual being evaluated for a possible
BRCA1/2 mutation. BRCA1 mutations have not been shown to consistently increase
risk for breast cancer in men whereas BRCA2 mutations have been shown to increase
the risk for male breast cancer. Accordingly, any case of male breast cancer, regard-
less of age at diagnosis, should prompt the offering of genetic counseling and consid-
eration of genetic testing for HBOC because of the overall low frequency of male
breast cancer in the general population and the markedly increased risk in men with
BRCA2 mutations. Kessler and colleagues (personal communication, 2007) found
that among individuals at increased risk for heritable colon cancer, an equal distribu-
tion of paternal and maternal transmission of deleterious (and autosomal) genes was
found. However, among individuals at increased risk for HBOC, an approximately
70:30 (maternal to paternal) distribution was found when an equal ratio would have
114 Shulman

been predicted (BRCA1/2 are autosomal). Families with either few members or few
females pose a barrier to accurate risk assessment, as affected females provide the
main evidence of the existence of a deleterious BRCA1/2 mutation. Kessler’s study
(personal communication) shows that in many cases, affected females in the paternal
lineage are either ignored or not considered on an equal basis with affected members
from the maternal lineage because of a misperception that HBOC is a disease of
women, and that genetic events in the paternal families of putative BRCA1/2 mutation
carriers do not play as important a role in the assessment of risk as those affected indi-
viduals in the maternal lineage.
Mutations in BRCA1/2 confer a markedly increased risk for developing breast
cancer and EOC, with BRCA1 and BRCA2 mutations both being associated with an
approximately 85% to 90% risk for developing breast cancer by the age of 70
(Figs. 1 and 2).18,19 However, whereas BRCA1/2 mutations are associated with
a markedly elevated risk for developing EOC, BRCA1 mutations are associated with
a higher risk for developing EOC than BRCA2 mutations (see Figs. 1 and 2). Risch
and colleagues20 found 60 germline mutations in BRCA1/2 among 649 unselected
cases of EOC; 39 were in BRCA1 and 21 in BRCA2. Satagopan and colleagues21
found that carriers of either of the 2 BRCA1 founder mutations in the Ashkenazi Jewish
population (185delAG and 5382insC) were estimated to have a 37% risk for devel-
oping EOC by the age of 70 years, whereas those carrying the founder BRCA2 muta-
tion (6174delT) were estimated to have a 21% risk. Other clinical differences between
the 2 BRCA1/2 gene mutations include an approximately 100-fold increased risk for
male breast cancer among BRCA2 mutation carriers with only a potentially slight
increased risk for male breast cancer among BRCA1 mutation carriers.22 In addition,
an increased risk for early-onset prostate and pancreatic cancer among BRCA2 muta-
tion carriers has been observed in some studies,8,23 whereas other studies of high-risk
prostate cancer families have observed little impact of BRCA2 mutations.24 In addi-
tion, a marked increased risk for pancreatic and gastric cancers in BRCA1 mutation
carriers has been reported25; of interest is that Risch and colleagues8 similarly
reported an increased risk for pancreatic and gastric cancers in BRCA1 and BRCA2
carriers, although they found the risk for pancreatic cancer to be higher among
BRCA2 carriers and the risk for gastric cancer to be higher in BRCA1 carriers. Finally,
although most of the morbidity and mortality associated with BRCA1/2 mutations has

Fig. 1. Age-related risk for breast and ovarian cancers associated with BRCA1 mutations.
(Adapted from Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1
mutation carriers. J Natl Cancer Inst 2002;94:1365–72; with permission.)
 Hereditary Breast and Ovarian Cancer 115

Fig. 2. Age-related risk for breast and ovarian cancers associated with BRCA2 mutations.
(Adapted from The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation
carriers. J Natl Cancer Inst 1999;91(15):1310–6; with permission.)

been focused on the increased risk for breast and ovarian cancers and other malig-
nancies, Mai and colleagues26 report a significantly increased risk for noncancer
mortality among BRCA1/2 mutation carriers, thus potentially adding another consider-
able medical and emotional issue to be addressed by genetic counselors providing
counseling to individuals at increased risk for having BRCA1/2 mutations.
Lynch Syndrome
CRC is the third most common type of cancer in the United States, with more than
140,000 new cases diagnosed each year. LS is the most common hereditary form
of CRC and is believed to account for up to 3% of all cases; with this projected
frequency of 1 out of every 35 individuals with CRC having LS, more than 28,000
new cases of LS will occur worldwide in 2010.27 This does not include individuals at
increased risk for CRC because of a positive family history; familial CRC, defined as
2 or more first-degree relatives with CRC, is thought to account for up to 20% of all
cases of CRC.27 If the impact of germline mutations and family history affect the
frequency of CRC and associated malignancies to this degree, the failure to assess
family history and to identify at-risk individuals to allow for earlier detection and inter-
vention programs clearly places a considerable number of people at risk for devel-
oping malignancies that could have ostensibly been prevented. As such, the value
of genetic counseling and testing for LS in at-risk individuals seems to be a relatively
straightforward and important step in reducing the risk for CRC and other associated
Lynch malignancies.
As with other cancer susceptibility syndromes, LS is associated with an increased
risk for cancers in multiple organs including endometrial, urogenital, pancreatic and
biliary tract, and EOC. Of note is that more recent study of Lynch families shows
that female members of these families have a higher cumulative lifetime risk for devel-
oping endometrial cancer than for developing colorectal cancer.27 Women who carry
a germline mutation for LS have a 20% to 60% lifetime risk of developing endometrial
cancer; Aarnio and colleagues28 reported standardized incidence ratios of 68% and
62%, respectively, in LS individuals with mutations in MLH1 or MSH2. Banno and
colleagues29 reported the frequency of microsatellite instability markers among 38
cases of endometrial cancers from individuals with familial clustering of cancers
(endometrial and other cancers) to be 31.6%, and Mathews and colleagues30 found
116 Shulman

immunohistochemical evidence of mismatch repair deficiency in 34% of newly diag-

nosed endometrial cancer patients younger than 50 years, indicating an important
pathophysiological role for abnormal DNA mismatch repair in the pathogenesis of
endometrial cancer. Counselors and clinicians who care for women with endometrial
cancer or their families must thus be mindful of the potential for LS in women with
endometrial cancer, especially those with family histories of other LS-associated
malignancies or with clinical presentations that would be suggestive of a heritable
predisposition to cancer development (eg, early age of diagnosis).
Watson and colleagues13 reported the lifetime risk (up to age 70 years) for extrac-
olonic tumors among a total of over 6000 LS mutation carriers, probable mutation
carriers (with CRC and/or endometrial cancer), and first-degree relatives of these 2
cohorts to be 8.4% for urologic tract cancers, with risks higher for males and MSH2
families. Despite the high risk for developing EOC among women with or at risk for
LS, LS mutations account for a relatively small proportion of all cases of EOC.31
EOCs associated with BRCA1/2 mutations are mostly serous in nature; however, LS
mutations are associated with a variety of ovarian cancer epithelial malignancies
including endometrioid and clear cell cancers. Of note, while most cases of ovarian
cancer in LS families are malignant epithelial tumors, most are well or moderately
differentiated and are International Federation of Gynecology and Obstetrics (FIGO)
Stage I or II at the time of diagnosis. This is in sharp contrast to BRCA mutation-asso-
ciated tumors, which tend to present in a more advanced stage and be more poorly
differentiated. Most of the Lynch families with EOC who were studied were found to
have germline mutations of the MLH1 or MSH2 genes.32 However, Cederquist and
colleagues33 reported a high frequency of a variety of EOC in Swedish women with
MSH6 mutations, with an estimated 33% lifetime risk of developing EOC in this
Swedish cohort. As with other cancer susceptibility genes, certain mutations in partic-
ular populations may exert a different impact on cancer risk than that typically
observed in the general population (ie, founder mutations). However, similar to women
with BRCA1/2 mutations, women with Lynch mutations tend to develop EOC at
a younger age (fifth decade) than sporadic cases of EOC (seventh decade). Watson
and colleagues13 also reported cases of cancers of the brain, small bowel, stomach,
biliary tract, and breast in their cohort, though with considerably lower frequencies.
The diagnosis of LS is made by detecting a mutation in an MMR gene.27 While there
is little controversy concerning increased surveillance for carriers of MMR mutations,
there is controversy concerning the approach to screening for such mutations. This
controversy revolves around uncertainties regarding whether the prevalence of
MMR mutations is sufficient to warrant large-scale screening, the trade-offs between
screening all patients with CRC versus targeted screening of certain high-risk groups
characterized by early age of diagnosis, family history, and tumor histology, and
whether to recommend immunohistochemistry (IHC) or MSI as the primary screening
tool.34 As such, unlike the detection of BRCA1/2 mutations, it is not the standard of
care to test every CRC or Lynch-associated cancer patient for germline mutations
in the MMR genes. It is currently recommended that a comprehensive family history
of cancers of all anatomic sites be obtained, with attention paid to the cardinal features
of LS.

ASSESSING CANCER RISK

Cancer risk assessment is a process by which individuals are identified who are at
increased risk for a hereditary or familial cancer and are offered a different approach
to prevention and screening than that which is offered to individuals in the general
 Hereditary Breast and Ovarian Cancer 117

population. Such altered interventions for high-risk individuals can range from an
earlier initiation of screening, such as the initiation of mammography before the age
of 40 years in women with a BRCA1/2 mutation, to the incorporation of screening
protocols not offered to non–high-risk individuals, such as the use of regular breast
magnetic resonance imaging (MRI) examinations in women with BRCA1/2 mutations.
The detection of a deleterious mutation may also prompt a novel or unique approach
to prevention, such as the consideration of oral contraceptive use to reduce the risk for
EOC in women with BRCA1/2 mutations, prophylactic colectomy in individuals with
mutations in DNA repair genes (LS), and prophylactic premenopausal salpingoophor-
ectomy in women with BRCA1/2 mutations. However, not all preventative measures
offered to high-risk individuals are necessarily extreme or extirpative in nature; for
example, women at increased risk for EOC are likely to be encouraged to breastfeed
or consider bilateral tubal ligation once childbearing has been completed as a way to
reduce the risk for EOC without increasing the risk for breast cancer.4,35 What is clear
is that the identification of high-risk individuals, whether as result of inheriting a delete-
rious mutation or because of a extensive family history of cancer, allows for the
offering of risk reduction strategies that have been shown to prolong lives and improve
quality of life for high-risk individuals.36 This is the rationale for the current approach to
cancer genetic counseling and risk assessment.

HBOC
Until an inexpensive and facile method becomes available that provides information
on an individual’s complete genome, there will controversies as to who is offered
genetic counseling and genetic testing to determine whether a deleterious mutation
in a tumor suppressor gene in present and is adversely affecting risk of developing
malignancy. The United States Preventative Services Task Force (USPSTF) put forth
guidelines in 200537 recommending that only women at high risk for having a delete-
rious BRCA1/2 mutation be offered counseling and testing. The USPSTF defined high-
risk women as those non-Ashkenazi Jewish women with 2 first-degree relatives with
breast cancer, 1 of whom received the diagnosis at age 50 years or younger; a combi-
nation of 3 or more first- or second-degree relatives with breast cancer regardless of
age at diagnosis; a combination of both breast and ovarian cancer among first- and
second-degree relatives; a first-degree relative with bilateral breast cancer; a combi-
nation of 2 or more first- or second-degree relatives with ovarian cancer regardless of
age at diagnosis; a first- or second-degree relative with both breast and ovarian
cancer at any age; and a history of breast cancer in a male relative. For women of
Ashkenazi Jewish heritage, an increased-risk family history includes any first-degree
relative (or 2 second-degree relatives on the same side of the family) with breast or
ovarian cancer. Based on these criteria, it was estimated that about 2% of adult
women in the general population have an increased-risk family history and should
be offered counseling and testing. Women with none of these family history patterns
have a low probability of having a deleterious mutation in BRCA1 or BRCA2 genes,
and the routine offer of counseling and testing to such low-risk individuals is not
recommended.
The USPSTF guidelines are just one attempt to quantify risk and identify those indi-
viduals who would most benefit from counseling and genetic testing. Other
approaches to quantifying risk include the popular Gail Model, as well as BRCA Pro
and the most recent breast cancer risk assessment tool from the National Cancer
Institute, the Breast Cancer Assessment Tool (www.cancer.gov; Table 2). All of these
methods are meant to be used by clinicians to determine breast cancer risk and take
118 Shulman

Table 2
Questions in the Breast Cancer Assessment Tool from the National Cancer Institute, last
modified April 28, 2008 (Click a question number for a brief explanation, or read all
explanations)

1. Does the woman have a medical history of any breast cancer or of

ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS)?
2. What is the woman’s age?
This tool only calculates risk for women 35 years of age or older

3. What was the woman’s age at the time of her first menstrual
period?

4. What was the woman’s age at the time of her first live birth of
a child?

5. How many of the woman’s first-degree relatives—mother, sisters,

daughters—have had breast cancer?

6. Has the woman ever had a breast biopsy?

6a. How many breast biopsies (positive or negative) has the woman
had?
6b. Has the woman had at least one breast biopsy with atypical
hyperplasia?

7. What is the woman’s race/ethnicity?

From Available at: http://www.cancer.gov. Accessed March 1, 2010.

into account a variety of demographic, family and personal history, and medical
history to arrive at an adjusted risk for developing breast cancer. Indeed, newer risk
assessment tools include factors other than personal and family history and are
considered to provide a more accurate assessment of risk by including such param-
eters as breast density, measurements of serum estradiol and androgens, body mass
index, and history of fracture and height loss.38 Those women found to be at increased
risk, usually considered to be a lifetime breast cancer risk of 20% to 25% or greater,
are typically offered counseling and genetic testing, as well as different screening
interventions such as annual breast MRI examinations.
Recent guidelines from the American College of Obstetricians and Gynecologists2
and the Society of Gynecologic Oncologists1 have clarified the need for clinicians to
incorporate risk assessment into their practices to identify those women who may
benefit from counseling and testing. Although these guidelines and recommendations
do not promote a more expansive role for genetic testing, they do raise awareness of
the marked increased risk of cancer development in individuals with tumor suppressor
gene mutations and with family members with certain malignancies. The guidelines
thus serve to encourage clinicians to incorporate cancer risk assessment, ranging
from a detailed family history to the use of a risk assessment tool such as the Gail
model or the Breast Cancer Risk Assessment Tool, and provide individuals at
increased risk for cancer to consider counseling, testing, and more appropriate
screening options. In this regard it is hoped that if such recommendations increase
the number of people undergoing genetic testing, it is as result of more people at
high risk recognizing their increased risk for developing cancer, and clinicians
 Hereditary Breast and Ovarian Cancer 119

choosing to further evaluate this risk with genetic testing rather than a greater (and
inappropriate) concern for developing such malignancies in the low-risk population.
Lynch Syndrome
Assessing an individual or a family for LS is accomplished by determining whether the
history meets Amsterdam II criteria (Table 3). If a family history is suggestive of LS but
the criteria cannot be met because of family size or other factors, consideration of risk
can be accomplished using revised Bethesda criteria (Table 4). Women with Lynch
mutations do not have a marked increased risk for developing breast cancer; as
such, family histories with multiple family members with ovarian cancer and no cases
of breast cancer, but having family members with Lynch-associated malignancies (eg,
colorectal cancer, endometrial cancer) should first be evaluated for MMR mutations
rather than BRCA1/2 mutations.39
Individuals who meet Amsterdam II criteria are evaluated by obtaining peripheral
blood for direct sequencing of the MLH1 and MSH2 genes. For those individuals
whose families do not meet Amsterdam criteria but do meet Bethesda criteria, first
evaluating tumor tissue for MSI and IHC (before mutation testing) is the preferred
approach for screening at-risk individuals. MSI testing and IHC appear to provide
concordant information, as Vasen and colleagues40 reported a 93% concordance
between the 2 tests in colon cancer specimens. This approach is associated with
high (90%–95%) sensitivity for detecting MMR gene mutation carriers,34 but as with
IHC, it provides no information as to which gene is mutated and thus which malig-
nancy that individual may have the highest risk for developing. As such, the diagnosis
of LS currently proceeds in a stepwise approach27:

1. Clinical suspicion from early-onset cancer or family history

2. Amsterdam II criteria assessment. If positive, germline mutation testing. If negative,
3. Bethesda criteria. If positive,
4. MSI testing. If MSI-High (MSI-H), germline mutation testing.

Unfortunately, Amsterdam II and Bethesda criteria have limitations for identifying

individuals at increased risk for LS. Both sets of criteria are based on CRC being
the preeminent malignancy; while the new criteria do recognize the role of extracolonic
malignancies, it is not clear how these criteria would work in the context of an indi-
vidual or family presenting with extracolonic malignancies but not CRC. While
Bethesda criteria work best to determine which tumors require further testing, individ-
uals with small pedigrees as well as those with a predominance of familial endometrial
cancer may not be well served by even these more recent guidelines.41

Table 3
Amsterdam II criteria for Lynch syndrome

At least 3 relatives with an HNPCC cancer: Colorectal, endometrial, stomach, ovary,

ureter/renal pelvis, brain, small
intestine, hepatobiliary tract, or
sebaceous tumor of skin
AND:
 One is a first-degree relative of the other 2
 At least 2 successive generations affected
 At least 1 of the HNPCC cancers was diagnosed at <50 y
 Familial adenomatous polyposis has been excluded

Abbreviation: HNPCC, hereditary nonpolyposis colorectal cancer.

120 Shulman

Table 4
Bethesda guidelines to determine which colorectal tumors should undergo MSI testing

Colorectal cancer diagnosed in a patient <50 y, or

Presence of synchronous or metachronous colorectal, or other HNPCC-associated tumor,
regardless of age, or
Colorectal cancer with the MSI-H histology diagnosed in patient <60 y, or
Colorectal cancer or HNPCC-tumor diagnosed <50 y in at least 1 first-degree relative, or
Colorectal cancer or HNPCC-associated tumor diagnosed at any age in 2 first-degree or second-
degree relatives

Another approach to screening individuals for LS is presented by the Society of

Gynecologic Oncologists (SGO), which combines some of the aforementioned issues
into the following committee report1 (adapted from Table 1 of Resnick and
colleagues41).

For patients with a 20% to 25% risk of LS, genetic risk assessment is strongly
recommended. Such patients include:
 Family pedigrees meeting Amsterdam criteria
 Patients with metachronous (define) or synchronous (define) CRC, endometrial
cancer or ovarian cancer before age 50
 Individuals with a first- or second-degree relative with a known germline mutation
in a mismatch repair gene.

For patients with a 5% to 10% risk for LS, genetic risk assessment may be helpful.
Such patients include:
 Patients with CRC or endometrial cancer diagnosed before age 50
 Patients with endometrial and/or ovarian cancer and a synchronous or meta-
chronous Lynch-associated tumor at any age
 Patients with CRC or endometrial cancer and a first-degree relative diagnosed
with a Lynch-associated malignancy before age 50
 Patients with CRC or endometrial cancer at any age with 2 or more first- or
second-degree relatives diagnosed with a Lynch-associated malignancy at
any age
 A patient with a first- or second-degree relative who meets the above criteria.

While the SGO recommendations present a clear identification of who may benefit
from genetic risk assessment and testing, they does not provide insight into what
testing should be offered.41 At present, colon cancer MSI testing and IHC are used
to triage patients to determine who should receive counseling and consideration of
gene sequencing, with IHC being an efficient and cost-effective tool in identifying
tumors with mismatch repair deficiency. However, the lack of emphasis on gyneco-
logic malignancies in the Amsterdam II and Bethesda criteria, as well as the recogni-
tion that having an age cut-off of 50 years below which IHC testing is routinely applied
to endometrial cancer cases, may be too low to adequately identify a sufficient
number of individuals with LS who present with endometrial cancer42,43 leads one
to consider an alternative approach to risk assessment and genetic testing for putative
LS individuals with endometrial cancer. Resnick and colleagues41 propose a screening
algorithm with endometrial cancer cases that uses an age cut-off of 60 years rather
than 50 years to determine which specimens are to be tested by IHC for MLH1,
 Hereditary Breast and Ovarian Cancer 121

MSH2, MSH6, and PMS2. Of the 1 in 5 specimens that have an abnormal IHC from this
expanded initial cohort, and adding to this individuals with considerable family histo-
ries or evidence of Cowden syndrome (see later discussion), approximately 12% of
cases would be referred for genetic counseling and gene sequencing.
Although there is currently no standard or conventional approach to either the iden-
tification of individuals at increased risk or screening and testing of those individuals
who may have inherited a mutated MMR gene, future technological advances,
including microarray assays, may make the development of diagnostic criteria or
screening algorithms obsolete. One of the major drawbacks to large-scale mutation
screening is the time and cost of such testing. The development of accurate and
less costly molecular analyses will surely promote a more widespread use of gene
testing for at-risk individuals for LS and other cancer susceptibility conditions.

OTHER HEREDITARY CANCER SYNDROMES INVOLVING BREAST

AND GYNECOLOGIC MALIGNANCIES
Cowden Syndrome
Cowden syndrome, or multiple hamartoma syndrome, is an autosomal dominant
condition characterized by the formation of multiple hamartomas in any organ of the
body and an increased risk for cancer. Pathognomonic features of Cowden syndrome
include facial trichilemmomas, acral keratosis, and oral papillomatous papules Individ-
uals with Cowden syndrome are at increased risk for developing a variety of benign
and malignant conditions, with more than 90% of individuals demonstrating muco-
cutaneous lesions.44 Germline mutations in PTEN (Phosphatase and TENsin homo-
logue deleted on chromosome TEN), located at 10q23.3, have been found in 85%
of Cowden syndrome individuals as well as in other rare and unrelated conditions
such as Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome. However,
these syndromes do share some common phenotypic features that have led to the
characterization of these conditions under the common classification of PHTS
(PTEN hamartoma tumor syndrome).45
In addition to the hamartomatous and dermatologic conditions, Cowden syndrome
is associated with an increased risk of a variety of malignancies. Lifetime risk for non-
medullary thyroid cancer is approximately 10%, with benign thyroid conditions also
increased in prevalence among affected individuals. Lhermitte-Duclos disease
(dysplastic gangliocytoma of the cerebellum) and renal cell carcinoma have also
been reported to be components of Cowden syndrome, although the exact frequency
of these 2 conditions among individuals with Cowden syndrome has not been well
defined. An increased risk of breast cancer has been reported among men with
Cowden syndrome.
Women with Cowden syndrome have an approximate 75% risk for benign breast
disease such as fibromas, fibroadenomas, and fibrocystic changes, as well as
a 25% to 50% lifetime risk for breast cancer.43 In addition, women with Cowden
syndrome have a 5% to 10% lifetime risk of endometrial cancer and an increased
risk of developing uterine fibroids.
Diagnosis of Cowden syndrome is achieved by demonstrating major and minor
criteria as put forth in the International Cowden Syndrome Consortium Operational
Criteria for the Diagnosis of Cowden Syndrome.46 Approximately 80% of individuals
who meet the diagnostic criteria are found to have mutations in PTEN. Because of
the considerable and varied increased risk for cancer development in individuals
with Cowden syndrome, extraordinary surveillance should be provided to detect
malignancies at an earlier and more treatable stage. Such screening may include
122 Shulman

a baseline thyroid examination and ultrasound at 18 years old with an annual thyroid
examination thereafter. A family history of renal cancer should prompt an annual
urinalysis and urine cytology along with a renal ultrasound. Women with Cowden
syndrome should begin annual clinical breast examinations at age 18 years with semi-
annual examinations beginning at age 25. Mammography should be offered at
approximately 25 to 30 years, or 10 years earlier than the youngest affected female
in the family. In addition, women with Cowden syndrome should be offered an annual
breast MRI on initiation of annual mammographic examinations. Men with Cowden
syndrome should have annual clinical breast examinations starting at age 25 to 30
years, with further evaluation based on the finding of palpable lesions. Annual endo-
metrial biopsies should be performed starting at age 35 to 40 years, or 10 years earlier
than the youngest affected individual in the family. This can also be augmented by an
annual endovaginal ultrasound examination in postmenopausal women.44 Endome-
trial cancer is amenable to risk reduction, and approaches to prevention should also
be discussed with affected individuals. Such measures can include oral contracep-
tives and intrauterine devices to reduce the incidence of endometrial cancer as well
as hysterectomy.47

Li-Fraumeni Syndrome
Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome estimated to
account for approximately 1% of hereditary breast cancer cases. Mutations in
TP53, a tumor suppressor gene located on 17p13.1, are the primary cause of LFS,
which is transmitted in an autosomal dominant fashion. In addition, families with
classic LFS phenotypes have also been found to have mutations in the CHEK2
gene, found on 22q12.2. Unlike TP53, CHEK2 encodes for a serine/threonine protein
kinase which phosphorylates p53, leading to cessation of mitosis and allowing DNA
repair; CHEK2 mutations thus promote the development of malignancy by inhibiting
DNA repair, similar to the MMR genes.
LFS is characterized by early-onset breast cancer, soft-tissue sarcomas, adreno-
cortical tumors, brain tumors, and leukemias. In some families with LFS, brain tumors,
adrenocortical tumors, and sarcomas may present in childhood. Additional tumors
reported in LFS families include ovary, pancreas, lung, stomach, melanoma, and
Wilms tumor.44 Similar to other cancer susceptibility conditions, LFS appears to
increase the risk of early development of cancer, with a 50% risk of cancer by age
40 years and a 90% risk of cancer by age 60.48 Screening and management of
patients at risk for LFS is challenging given the variety of early-onset malignancies
associated with this condition. In women, annual clinical breast examinations,
including MRI and mammography, should start at age 20 years, and consideration
of oral contraception use is warranted to reduce the risk of ovarian cancer, along
with an annual pelvic and abdominal ultrasound examination. However, there are no
published guidelines for screening LFS patients; clinicians should strongly consider
genetic counseling and testing (TP53 and CHEK2) for individuals and family members
with a considerable history of sarcomas and early-onset cancers.
Breast and other gynecologic cancers are found as associated malignancies in
other genetic syndromes (Table 5), all of which are rare and associated with a varied
spectrum of nonmalignant conditions and disorders. Syndromes associated with
ovarian cancer are rare and are usually associated with nonepithelial ovarian cancer,
although some cases of serous and mucinous EOC have been reported. Although
ovarian cancers and tumors have been reported in women with these genetic condi-
tions, the overall risk for developing EOC in women with these conditions seems to be
similar to that of the general population. However, the risk for developing breast and
 Hereditary Breast and Ovarian Cancer 123

Table 5
Genetic syndromes associated with breast and gynecologic cancers

Gene Gyn/Breast
Syndrome Inheritance (Chromosome) Clinical Features Cancer
Peutz-Jeghers AD STK11 (19) Melanocytic macules Sex cord-stromal
(mouth and lips); tumors; granulosa
polyps in GI tract; cell tumors; breast
increased risk of GI cancer
tract carcinoma
Ollier Sporadic/AD? PTHR1 (3) Multiple Granulosa cell
enchondromas; tumors
secondary
chondrosarcomas;
orthopedic
complications
Gorlin AD PTCH (9) Basal cell carcinoma Fibrosarcoma; also
of the skin before benign fibromas
age 30; jaw cysts;
vertebral
abnormalities
Ataxia- AR ATM (11q22.3) Delayed motor skill Breast cancer in
telangiectasia development, heterozygous
slurred speech, state
telangiectasias,
ALL, lymphoma
Hereditary diffuse AD CDH1(16q22.1) Early-onset gastric Lobular breast
gastric cancer cancer cancer
Li-Fraumeni AD TP53 (17p13) Early-onset multiple Breast cancer
CHEK2 (22q12) tumor types
especially
sarcomas, breast,
brain adrenal, and
leukemias
Cowden AD PTEN (10q23) Hamartomatous Breast cancer
lesions especially
skin, mucous
membranes,
breast, and
thyroid

Abbreviations: AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal reces-
sive; GI, gastrointestinal.

endometrial cancers may be increased in individuals affected with these syndromes.

Notwithstanding, evaluation of the pelvis by ultrasound or laparoscopy in cases of
pelvic masses, as well as mammography in affected women with breast masses, is
warranted.

COUNSELING

The past 2 decades have witnessed the identification of several genes that have been
associated with hereditable breast and gynecologic cancers, thereby promoting the
development of and need for cancer genetic counseling. Similar to conventional
genetic counseling for pediatric and prenatal conditions, cancer genetic counseling
124 Shulman

is geared to identifying individuals with cancer predisposition gene mutations as well

as those family and personal histories that affect the overall risk for development of
cancer. However, unlike conventional genetic counseling in which most individuals
or fetuses with a particular phenotype are likely to possess a deleterious gene or
abnormal chromosome complement, most cases of cancer, even those associated
with considerable family histories in individuals of high-risk ethnic and racial groups,
are not associated with the inheritance of cancer predisposition genes. Indeed, no
more than 10% of most types of cancer are associated with heritable conditions.49
Nonetheless, cancer genetic counseling has become a seminal part of the risk assess-
ment process; not only to identify those individuals with mutations in cancer predispo-
sition genes but also to reassure those individuals who have not inherited such
mutations, as well as to counsel those individuals who have not inherited specific
mutations but may still be at increased risk for developing malignancies.
The increased risk for developing cancer in women with mutations in cancer
susceptibility genes invariably begins with the inheritance of a germline mutation
within a tumor suppressor gene from either parent. Although gynecologic malignan-
cies can only occur in females, genes that predispose to the development of gyneco-
logic malignancies are usually autosomal in nature and thus can be inherited from
either parent. This concept is critical with regard to family history information, as
both parents can transmit deleterious gene mutations; accordingly, obtaining careful
and detailed family histories of an individual’s maternal and paternal families is vital to
developing an accurate risk assessment for an individual.
By definition, a germline mutation is present at conception; every cell of the indi-
vidual will have the gene mutation, a fact that is likely associated with the involvement
of multiple organs in many cancer susceptibility syndromes. However, the inheritance
of a mutated cancer susceptibility allele is only the first step (eg, 1 of 2 tumor
suppressor genes with no mutations and 1 gene with a mutation) in promoting the
development of a malignancy, and does not guarantee that an individual will go on
to develop a particular malignancy. The development of a heritable cancer, as well
as most other cancers, is postulated to be dependent on the occurrence of a second
genomic alteration.50 That an individual has inherited the first ‘‘step’’ serves to explain
why such individuals have a considerably higher risk for developing cancer than the
general population, as well as why cancer predisposition syndromes tend to present
with malignancies at an earlier age and with a higher frequency of bilaterality than what
usually occurs in the general population. Cancer is a disease of somatic cells;
however, if 2 (or more) independent events are needed for the cells to become malig-
nant, then inheriting the first step, as opposed to waiting for it to occur as a result of
some environmental event or exposure causing a somatic alteration, will surely
increase the likelihood of cancer occurring compared with those individuals who do
not inherit such mutations. The second (and any subsequent) step is invariably
somatic in nature, also explaining why not everyone who inherits a susceptibility
gene (ie, mutation in a tumor suppressor gene) develops the malignancy. Molecular
studies of cancers in individuals with malignancies arising from hereditary cancer
syndromes frequently show a loss of heterozygosity at the genomic position of the
tumor suppressor gene in tumor tissue. This loss of heterozygosity (both tumor
suppressor gene copies with a mutation) is the result of the second step, and is neces-
sary for the development of malignancies in individuals who have inherited certain
cancer susceptibility gene mutations.
There are numerous mechanisms that likely lead to this loss of heterozygosity and,
thus, the inactivation of the tumor suppressing gene. While cellular and nuclear
somatic events are common and mostly random processes by which genes and
 Hereditary Breast and Ovarian Cancer 125

chromosomes are altered, deleted, replaced, or rearranged without typically leading

to pathology, such changes in the presence of an inherited gene mutation in a tumor
suppressor gene can lead to the inactivation of tumor-suppressing gene function and
predispose that organ to undergo malignant transformation. This process is known as
monoallelic inheritance of a gene mutation with subsequent inactivation of the wild-
type allele and loss of heterozygosity. However, it is now recognized that some
individuals can inherit mutations in both alleles (either homozygous or compound
heterozygous), an uncommon occurrence known as inherited biallelic mutations,
which tend to present with a different clinical phenotype, including childhood cancers,
than what is usually associated with monoallelic (dominant) inheritance of mutations.51
It is interesting that while most hereditary cancer syndromes, including HBOC
syndrome, are transmitted in and present as a classic autosomal dominant inherited
condition, the requirement of a second step that inactivates the remaining normal
allele (biallelic inactivation) makes the cellular mechanism necessary for the promotion
of carcinogenesis recessive at a cellular level, which is also observed with biallelic
inheritance. However, the different phenotypes associated with biallelic inheritance
compared with monoallelic inheritance bespeak a difference in the molecular biology
of these 2 disease inheritance patterns, and may eventually provide valuable insight
into the molecular mechanisms of cancer development.
Nonetheless, most cancers, even those associated with considerable family histo-
ries, are not associated with germline mutations. Accordingly, an alternative mecha-
nism or mechanisms are likely responsible for the development of considerably
more cases of cancer than those currently associated with germline mutations in
cancer predisposition genes. Fasching and colleagues52 propose that cancer suscep-
tibility may be influenced by common low penetrance genetic polymorphisms, which
have been associated with common disorders such as diabetes. The delineation of
deleterious mutations in cancer susceptibility genes was a great leap forward in the
molecular and clinical elucidation of cancer development; however, further investiga-
tions are required into the molecular processes and clinical characteristics of cancer in
order to develop more effective screening, diagnostic, and therapeutic interventions
that are applicable to more cancers and considerably more people than are currently
affected by the identification of individuals at high risk for the development of heritable
malignancies.
Assuming one has provided accurate personal and family histories, counselors can
use a variety of approaches to assess risk for developing heritable cancers. Qualitative
and quantitative risk assessments are how counselors determine an individual’s risk
for possessing a deleterious mutation in a cancer susceptibility gene and for devel-
oping cancer. Qualitative risk assessment primarily uses family and personal histories
to determine an individual’s risk, and incorporates a variety of personal and environ-
mental factors including exposure to toxic substances, use of medications, pathology
reports, and lifestyle issues (eg, number of pregnancies, length of time breastfeeding,
and so forth) among others. An accurate qualitative assessment includes a detailed
personal and family history, supported by corroborated details of the individual’s
personal and family history. Such details will include, but are not limited to, age of
patient and family members, reproductive histories, histories of genetic disorders
and major illnesses, causes of death, and lifestyle issues (eg, obesity, oral contracep-
tive use) that could affect morbidity and mortality as well as increasing or decreasing
risk for cancer development. In addition, for family members with cancer, further detail
is needed including age of diagnosis, staging and grading of tumor, and years of
survival. This information should optimally be obtained from operative and pathology
reports as well as medical records. All of this information can be included into
126 Shulman

BRCAI (187de IAG)

paternal transmission

92 Overy 58 Breast d.70s d.80s

d.72 heart dx 80s

69 70 66 Breast 64
Overy 62

Breast 39 36 40

cancer History. Cancer Diagnosis = Overy

cancer History. Cancer Diagnosis = Breast

4 2

Fig. 3. Pedigree of individual with BRCA1 mutation (187delAG) in proband (arrowhead).

Transmission is through paternal side of family; father was the individual initially tested
and was found to carry the deleterious mutation.

a pedigree (Fig. 3), which provides an easy-to-access overview of the proband and his
or her family. Such information is critical even in the absence of genetic testing
outcomes. Søegaard and colleagues53 found that women with first-degree relatives
with EOC were at a significantly increased risk for developing EOC, especially early-
onset EOC.
Quantitative risk assessment employs risk assessment models (see section Assess-
ing Cancer Risk) to ascertain an individual’s risk for carrying a deleterious mutation in
a cancer susceptibility gene. While risk assessment models are widely used to assess
risk for certain cancers such as breast cancer, not all malignancies are amenable to
risk assessment by a model.54 As such, counselors usually use qualitative and quan-
titative approaches to determine an individual’s risk for carrying a deleterious cancer
susceptibility gene, and provide nondirective counseling concerning the option to
undergo genetic testing or to initiate particular screening, diagnostic, or preventative
measures.
In all counseling situations, counselors should also perform a psychosocial assess-
ment of their patients, as patients frequently face emotional stress and psychological
upset based on the findings of the counseling and genetic testing (if performed). Coun-
selors should obtain information from patients before counseling and risk assessment
concerning their expectations for the counseling session, the personal impact of the
cancer(s) in question, and the economic impact of undergoing counseling and testing;
the potential clinical outcomes, their relationship with relatives, and the ability to obtain
information from those relatives; and the desire to alter their lifestyle and initiate
preventative measures in case an increased risk for cancer is determined. Equally
important is the sense of the patient concerning the personal and familial implications
 Hereditary Breast and Ovarian Cancer 127

of positive or negative genetic testing results. Olaya and colleagues55 found that 50%
of individuals at increased risk for carrying a BRCA1/2 mutation chose not to undergo
genetic testing, with insurance coverage playing apparently no role in the decision to
undergo or forgo such testing. In this study the investigators sought to develop coun-
seling instruments that would better explain the benefits of testing to unaffected high-
risk individuals and to target those with a high-school level education as a strategy to
improve testing rates. One should consider that those individuals who chose to forgo
genetic testing in this study did choose to undergo genetic counseling because of an
increased risk for developing cancer. This study thus demonstrates that a variety of
psychosocial factors play a major role in determining not only decisions to obtain
counseling and testing but also specific choices in this informational process. Accord-
ingly, counselors must be aware of and work with these psychosocial issues if they are
to provide effective counseling and empower their patients to obtain all the information
that they seek.
Testing an individual for a deleterious mutation that occurs in a parent is a relatively
straightforward process; nonetheless, the emotional implications of either a positive or
negative result are complex, and should be addressed before testing as the emotional
impact of the testing outcomes may not necessarily be easy to predict and can
profoundly impact the counseling process. A good example of this is found in the
movie ‘‘In The Family’’ (J. Rudnick, Producer, Kartemquin Films, 2008), a film that
documents the life of a BRCA1 mutation carrier and details the lives of other individ-
uals at risk for or with heritable breast and ovarian tumors. In one scene, 3 daughters
are finding out their BRCA1 mutation status, having decided to get tested because
their mother has a deleterious BRCA1 mutation. Two daughters are found to have
inherited the mutation while the other is found to not carry the gene. Surprisingly, it
is the unaffected sibling who is most upset at the findings of the genetic testing.
Genetic risk assessment and testing may provide qualitative and quantitative analysis
to individuals at increased risk for developing cancer; however, the perception of that
risk by patients is driven by emotional and psychological factors that are considerably
affected by the individual’s experience with cancer. Another example of this is found in
the following patient case history:
A 32-year-old woman G3P3, a college-educated, married woman with 3 children
and not of Ashkenazi Jewish heritage, is referred for genetic counseling for cancer
risk assessment by a Gynecologic Oncologist who saw the patient after self-referral
for a bilateral salpingoophorectomy. The patient’s mother had died 2 years ago
from ovarian cancer at the age of 62; no other family members had ovarian cancer
but several family members in the paternal and maternal families had breast cancer,
with 2 paternal aunts and a first cousin with premenopausal breast cancer. After
extensive counseling was provided, testing was offered to her paternal aunts with
premenopausal breast cancer, who were found to carry no BRCA1/2 mutations.
Nevertheless, the patient chose to undergo BRCA1/2 sequencing and BART (genomic
rearrangement) testing, which revealed no deleterious mutations. Despite the reassur-
ing genetic testing results, the patient was resolute in her decision to undergo extirpa-
tive ovarian surgery, even after a frank discussion of the health concerns resulting from
premenopausal oophorectomy. When informed that her risk for developing breast
cancer was considerably higher than her risk for developing ovarian cancer, and
that bilateral mastectomy would be a risk-reducing approach to be considered, the
patient look horrified and stated that she would never consider removing her breasts
unless there was a malignancy.
In this situation, the patient’s personal experience with her mother’s ovarian cancer
far outweighed her considerably higher risk for breast cancer development based on
128 Shulman

her family history. Indeed, such personal experiences are frequently the reason for
certain behaviors and actions including seeking or avoiding genetic counseling,
obtaining genetic testing, initiating risk-reducing interventions, and undergoing
prophylactic surgeries. Many women in the Northwestern Ovarian Cancer Early Detec-
tion and Prevention Program (NOCEDPP) remain active participants in the program
even after they are found not to carry the deleterious gene that was associated with
a family member’s (usually a parent or sibling) cancer. The discovery and acceptance
of psychosocial factors in coping mechanisms, behavior modifications, and emotional
reactions to medical and nonmedical events by counselors can greatly assist the
counselor in providing accurate information that is best used by the patient.
The detection of a deleterious mutation provides a more clear determination of
one’s risk for developing cancer as well as presenting a variety of screening, diag-
nostic, and preventative algorithms to reduce the likelihood of cancer or to facilitate
an earlier detection of cancer at a stage more amenable to successful treatment. In
such cases, counselors need to be aware of the emotional implications of this finding
and help their patients cope with what some describe as a personal ‘‘Sword of Damo-
cles.’’ Conversely, the detection of no mutation, even in individuals with parents who
have mutations, can lead to unexpected emotional reactions including guilt, self-
loathing, and angst, frequently as result of the concern not that they were spared
but rather they were excluded from the cancer issues that beset their families. While
many individuals who find they possess no deleterious mutation show positive
emotions from relief to joy, assessing the psychosocial status of an individual at the
beginning of the counseling process will help avert unexpected and potentially
adverse reactions to risk assessment and genetic testing outcomes.
Finally, not everyone who undergoes genetic testing receives a definitive result indi-
cating the presence or absence of a deleterious mutation. Of those undergoing testing
for BRCA1/2 mutations, approximately 7% are found to have a variant of uncertain
significance (VUS). VUS are usually missense or potential splice site changes that
have not, as yet, been shown to be definitively associated with adverse clinical
outcomes. More than 1500 VUS have been identified, and are frequently identified
in individuals of minority ethnic population. Most VUS have only been reported in 1
to 2 individuals, making further analysis of the clinical impact of VUS challenging.
Once a VUS is identified, further analyses such as segregation analysis or study vari-
ants in multiple unrelated individuals are applied in an attempt to characterize the VUS
as clinically relevant (favor deleterious) or irrelevant (favor polymorphism).56 However,
small sibships and family sizes as well as few individuals with any particular VUS
impede the mathematical estimation needed to better characterize the clinical impact
of a specific VUS.
The finding of a VUS is obviously a difficult clinical outcome that can lead to consid-
erable emotional distress and angst concerning the clinical implications of the genetic
test result. In such situations, counselors must use their skills to provide a clear and
measured overview of the meaning and implication of the test, and provide emotional
support for a patient who may be distraught because of the inability to obtain a defin-
itive assessment of her risk for developing cancer.

RISK PERCEPTION AND OTHER COUNSELING ISSUES

Not surprisingly, Rantala and colleagues57 report that prior to genetic counseling,
most individuals harbor misperceptions concerning their risk, with their perception
invariably being an overestimation of their actual risk. The investigators also found
that there was a trend to a more accurate perception of risk following genetic
 Hereditary Breast and Ovarian Cancer 129

counseling, and that the importance of preventative programs was well understood.
According to Rantala and colleagues, cancer anxiety was prevalent and was associ-
ated with most of the inaccuracy associated with risk perception by all study partici-
pants. However, the investigators also found that cancer anxiety decreased after
genetic counseling, demonstrating yet another important clinical benefit of genetic
counseling for individuals at increased risk for cancer susceptibility syndromes.
Similar findings were reported in an Italian study by Caruso and colleagues,58 who
also found an overestimation of cancer risk by women in this survey study compared
with BRCApro calculated estimates, with more pronounced inaccuracy and misper-
ception reported by low-risk women than high-risk women.
The anxiety observed in many people undergoing cancer genetic counseling clearly
has the potential to taint the counseling process by not permitting information to be
properly interpreted and analyzed by the counselee. Although this is not a unique or
novel phenomenon in genetic counseling, it may be something that is not frequently
encountered by medical generalists and specialists without formal genetics training.
Phelps and colleagues59 report on the development of a quantitative tool (the Genetic
Risk Assessment Coping Evaluation, or GRACE) to assess the degree of distress
associated with the genetic counseling risk assessment process and identify the range
of coping strategies used to lessen the distress being experienced by the patient.
Other tools are also available; it is important to recognize that the anxiety that leads
individuals to seek counseling, and likely hinders others from initiating counseling
and risk assessment, can adversely affect the counseling process if the counselor
does not recognize the anxiety and does not use techniques to help individuals gain
a more accurate perception of their risk and the steps to be taken, if available, to
reduce their risk for developing cancer.
Morgan and colleagues60 found that among women who had undergone genetic
counseling and were at high risk for HBOC, all agreed that following cancer screening
recommendations was better than not following such recommendations; none felt that
the recommendations were difficult to follow and all believed that screening would
help them stay healthy. More than half of the respondents (57%) believed that
following the screening recommendations would prevent cancer. None reported any
perceived barriers to care, although more than one-third (38%) felt that reminders
would help and 10% needed assistance in following through with care. Although
genetic counseling can never provide all the information needed for a decision in
a manner that all patients can understand, the process of genetic counseling has
clearly been shown to empower individuals to make informed decisions about critical
medical issues in their lives and to provide the emotional support needed by many to
follow through with their decisions.

SUMMARY

The information accrued from the Human Genome Project will surely be a revolutionary
step in a process of developing new medical screening, diagnostic, and therapeutic
paradigms. The delineation of the genetic and genomic characteristics of cancer,
and in particular solid tumors, has altered the preventative, detection, and therapeutic
approaches to these malignancies over the past decade. While much attention has
been paid to the identification of tumor suppressor genes and the mutations that result
in marked increases in cancer risk, there is recognition that somatic genetic alterations
in tumor cells provide valuable information that is now applicable to improving clinical
outcomes. For example, HER2 status in breast cancer tissue is now an important
determinant in choosing the most effective chemotherapeutic regimen.61
130 Shulman

This burgeoning role of genetics and genomics in the development and treatment of
cancer requires professionals to be able to integrate current evidence with the ability
to obtain critical information from patients and provide the necessary support to facil-
itate the process by which individuals at high risk are identified and offered novel
screening, diagnostic, and preventative interventions to reduce the risk of cancer
and improve overall clinical outcomes. Cancer genetic counseling is the process
currently used to identify high-risk individuals and provide them with information
and emotional support to facilitate their decision-making process. Although techno-
logical advances may eventually alter the cancer genetic counseling process, for
now and the foreseeable future this will be how patients are best served in their search
for answers concerning their risks for developing cancer, and in the delineation of
improved interventions to prevent and treat an expanding number and variety of
malignancies.

REFERENCES

1. Lancaster JM, Powell CB, Kauff ND, et al. SGO Committee Statement: Society of
Gynecologic Oncologists Education Committee statement on risk assessment for
inherited gynecologic cancer predispositions. Gynecol Oncol 2007;107:159–62.
2. ACOG Practice Bulletin. Hereditary breast and ovarian cancer syndrome. Gyne-
col Oncol 2009;113:6–11.
3. Lynch HT, Casey MJ, Snyder CL, et al. Hereditary ovarian carcinoma: heteroge-
neity, molecular genetics, pathology, and management. Mol Oncol 2009;3:
97–137.
4. Kjaer SK, Mellemkjaer L, Brinton LA, et al. Tubal sterilization and risk of ovarian,
endometrial and cervical cancer. A Danish population-based follow-up study of
more than 65,000 sterilized women. Int J Epidemiol 2004;33:596–602.
5. Palma MD, Domchek SM, Stopfer J, et al. The relative contribution of point muta-
tions and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast
cancer families. Cancer Res 2008;68:7006–14.
6. Bellosillio B, Tusquets I. Pitfalls and caveats in BRCA sequencing. Ultrastruct
Pathol 2006;30:229–35.
7. Whittemore AS, Gong G, Imyre J. Prevalence and contribution of BRCA1 muta-
tions in breast cancer and ovarian cancer: results from 3 US population-based
case-control studies of ovarian cancer. Am J Hum Genet 1997;60:496–504.
8. Risch HA, McLaughlin JR, Cole DEC, et al. Population BRCA1 and BRCA2 muta-
tion frequencies and cancer penetrances: a Kin-Cohort Study in Ontario,
Canada. J Natl Cancer Inst 2006;98:1694–706.
9. Metcalfe KA, Poll A, Royer R, et al. Screening for founder mutations in BRCA1
and BRCA2 in unselected Jewish women. J Clin Oncol 2010;28:387–91.
10. Mikaelsdottir EK, Valgeirsdottir S, Eyfjord JE, et al. The Icelandic founder muta-
tion BRCA2 999del5: analysis of expression. Breast Cancer Res 2004;6:R284–90.
11. Pal T, Permuth-Wey J, Sellers TA. A review of the clinical relevance of mismatch-
repair deficiency in ovarian cancer. Cancer 2008;113:733–42.
12. Wijnen J, de Leeuw W, Vasen H, et al. Familial endometrial cancer in female
carriers of MSH6 germline mutations. Nat Genet 1999;23:142–4.
13. Watson P, Vasen HFA, Mecklin J-P, et al. The risk of extra-colonic, extra-endome-
trial cancer in the Lynch syndrome. Int J Cancer 2008;123:444–9.
14. Aaltonen LA, Peltomaki P, Leach FS, et al. Clues to the pathogenesis of familial
colorectal cancer. Science 1993;260:812–6.
 Hereditary Breast and Ovarian Cancer 131

15. Ramus SJ, Gayther SA. The contribution of BRCA1 and BRCA2 to ovarian cancer.
Mol Oncol 2009;3:138–50.
16. Bewtra C, Watson P, Conway T, et al. Hereditary ovarian cancer: a clinicopatho-
logical study. Int J Gynecol Pathol 1992;11:180–7.
17. Antoniou AC, Gayther SA, Stratton JF, et al. Risk models for familial ovarian and
breast cancer. Genet Epidemiol 2000;18:173–90.
18. Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1
mutation carriers. J Natl Cancer Inst 2002;94:1365–72.
19. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers.
J Natl Cancer Inst 1999;91(15):1310–6.
20. Risch HA, McLaughlin JR, Cole DEC, et al. Prevalence and penetrance in germ-
line BRCA1 and BRCA2 mutations in a population series of 649 women with
ovarian cancer. Am J Hum Genet 2001;68:700–10.
21. Satagopan JM, Boyd J, Kauff ND, et al. Ovarian cancer risk in Ashkenazi
Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res 2002;8:
3776–81.
22. Levy-Lahad E, Friedman E. Cancer risks among BRCA1 and BRCA2 mutation
carriers. Br J Cancer 2007;96:11–5.
23. Mohammad HB, Apffelstaedt JP. Counseling for male BRCA mutation carriers—
a review. Breast 2008;17:441–50.
24. Ostrander EA, Udler MS. The role of the BRCA2 gene in susceptibility to prostate
cancer revisited. Cancer Epidemiol Biomarkers Prev 2008;17:1843–8.
25. Brose M, Rebbeck T, Calzone K, et al. Cancer risk estimates for BRCA1 mutation
carriers identified in a cancer risk evaluation program. J Natl Cancer Inst 2002;
94:1359–65.
26. Mai PL, Chatterjee N, Hartge P, et al. Potential excess mortality in BRCA1/2 muta-
tion carriers beyond breast, ovarian, prostate and pancreatic cancers, and mela-
noma. PLoS One 2009;4(3):e4812. DOI: 10.1371/journal.pone.0004812.
27. Lynch HT, Lynch PM, Lanspa SJ, et al. Review of the Lynch syndrome: history,
molecular genetics, screening, differential diagnosis, and medicolegal ramifica-
tions. Clin Genet 2009;76:1–18.
28. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA
mismatch repair genes. Int J Cancer 1999;81:214–8.
29. Banno K, Yanokura M, Kobayashi Y, et al. Endometrial cancer as a familial tumor:
pathology and molecular carcinogenesis [review]. Curr Genomics 2009;10:
127–32.
30. Mathews KS, Estes JM, Connor MG, et al. Lynch syndrome in women less than 50
years of age with endometrial cancer. Obstet Gynecol 2008;111:1161–6.
31. Malander S, Rambech E, Kristoffersson U, et al. The contribution of the hereditary
nonpolyposis colorectal cancer syndrome to the development of ovarian cancer.
Gynecol Oncol 2006;101:238–43.
32. Russo A, Calo V, Bruno L, et al. Hereditary ovarian cancer. Crit Rev Oncol Hem-
atol 2009;69:28–44.
33. Cederquist K, Emanuelsson M, Wiklund F, et al. Two Swedish founder MSH6
mutations, one nonsense and one missense, conferring high cumulative risk of
Lynch syndrome. Clin Genet 2005;68:533–41.
34. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch
syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:
5783–8.
35. Jordan SK, Siskind V, Green C, et al. Breastfeeding and risk of epithelial ovarian
cancer. Cancer Causes Control 2010;21:109–16.
132 Shulman

36. Kurian AW, Sigal BM, Plevritis SK. Survival analysis of cancer risk reduction strat-
egies for BRCA1/2 mutation carriers. J Clin Oncol 2010;28:222–31.
37. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA muta-
tion testing for breast and ovarian cancer susceptibility: recommendation state-
ment. Ann Intern Med 2005;143:355–61.
38. Santen RJ, Boyd NF, Chlebowski RT, et al. Critical assessment of new risk factors
for breast cancer: considerations for development of an improved risk prediction
model. Endocr Relat Cancer 2007;14:169–87.
39. South SA, Vance H, Farrell C, et al. Consideration of hereditary nonpolyposis
colorectal cancer in BRCA mutation-negative familial ovarian cancers. Cancer
2009;115:324–33.
40. Vasen HF, Hendriks Y, de Jong AE, et al. Identification of HNPCC by molecular
analysis of colon and endometrial tumors. Dis Markers 2004;20:207–13.
41. Resnick KE, Hampel H, Fishel R, et al. Current and emerging trends in Lynch
syndrome identification in women with endometrial cancer. Gynecol Oncol
2009;114:128–34.
42. Goodfellow PJ, Buttin BM, Herzog TJ, et al. Prevalence of defective DNA
mismatch repair and MSH6 mutation in an unselected series of endometrial
cancers. Proc Natl Acad Sci U S A 2003;100:5908–13.
43. Hampel H, Panescu J, Lockman J, et al. Comment on: screening for Lynch
syndrome (hereditary nonpolyposis colon cancer) among endometrial cancer
patients. Cancer Res 2007;62:9603.
44. Allain DC. Genetic counseling and testing for common hereditary breast cancer
syndromes. J Mol Diagn 2008;10:383–95.
45. Orloff MS, Eng C. Genetic and phenotypic heterogeneity in the PTEN hamartoma
tumour syndrome. Oncogene 2008;27:5387–97.
46. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic
criteria. J Med Genet 2000;37:828–30.
47. Shulman LP. Advances in female hormonal contraception: current alternatives to
oral regimens. Treat Endocrinol 2003;2:247–56.
48. Lustbader ED, Williams WR, Bondy ML, et al. Segregation analysis of cancer in fami-
lies of childhood soft-tissue-sarcoma patients. Am J Hum Genet 1992;51:344–56.
49. Kinsler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;
87:159–70.
50. Knudson AG. Two genetic hits (more or less) to cancer. Nat Rev Cancer 2001;1:
157–62.
51. Rahman N, Scott RH. Cancer genes associated with phenotypes in monoallelic
and biallelic mutation carriers: new lessons from old players. Hum Mol Genet
2007;16(Spec No 1):R60–6.
52. Fasching PA, Gayther S, Pearce L, et al. Role of genetic polymorphisms and
ovarian cancer susceptibility. Mol Oncol 2009;3:171–81.
53. Søegaard M, Frederiksen K, Jensen A, et al. Risk of ovarian cancer in women with
first-degree relatives with cancer. Acta Obstet Gynecol Scand 2009;88:449–56.
54. Prucka SK, McIlvried DE, Korf BR. Cancer risk assessment and the genetic coun-
seling process: using hereditary breast and ovarian cancer as an example. Med
Princ Pract 2008;17:173–89.
55. Olaya W, Esquivel P, Wong JH, et al. Disparities in BRCA testing: when insurance
coverage is not a barrier. Am J Surg 2009;198:562–5.
56. Spearman AD, Sweet K, Zhou X-P, et al. Clinically applicable models to charac-
terize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol 2008;
26:5393–400.
 Hereditary Breast and Ovarian Cancer 133

57. Rantala J, Platten U, Lindgren G, et al. Risk perception after genetic counseling in
patients with increased risk of cancer. Hered Cancer Clin Pract 2009;7:15.
58. Caruso A, Vigna C, Marozzo B, et al. Subjective versus objective risk in genetic
counseling for hereditary breast and/or ovarian cancers. J Exp Clin Cancer Res
2009;28:157.
59. Phelps C, Bennett P, Jones H, et al. The development of a cancer genetic-
specific measure of coping: the GRACE. Psychooncology 2009. DOI: 10.1002/
pon.1629.
60. Morgan D, Sylvester H, Lucas FL, et al. Perceptions of high-risk care and barriers
to care among women at risk for hereditary breast and ovarian cancer following
genetic counseling in the community setting. J Genet Couns 2009. DOI: 10.1007/
s10897-009-9261-9.
61. Osako T, Horii R, Matsuura M, et al. High-grade breast cancers include both
highly sensitive and highly resistant subsets to cytotoxic chemotherapy. J Cancer
Res Clin Oncol 2010 Feb 9. [Epub ahead of print].