BASIC SCIENCE

The genetics of breast cancer The clustering of breast cancer in families is almost entirely
due to genetic variation rather than shared lifestyle or environ-
ment. The risk of developing breast cancer is twice as high in
Alexandra J Murray
women who have an affected first-degree relative (FDR) than
D Mark Davies women in the general population. The majority of the genetic
risk is due to low-risk or moderate-risk susceptibility alleles, each
of which confers only a very small increased risk in isolation but
which in combination may have quite a significant effect.1
Abstract Currently these low-penetrance genes cannot be used clinically
Breast cancer is the commonest cancer affecting women. A family history
in the management of individual patients but they may, in time,
of breast cancer increases a woman’s lifetime risk of developing the
be helpful in the context of population screening programmes for
disease. Most of the genetic risk is due to low-risk and moderate-risk
disease prevention. Pathogenic variants in high-penetrance genes
susceptibility alleles rather than high-penetrance genes such as BRCA1
such as BRCA1 and BRCA2 (Table 1) confer a high risk of breast
and BRCA2. Pathogenic variants in these two tumour suppressor genes
cancer, but these variants are rare and only account for a small
only account for about 2% of all breast cancers. Female carriers of the
percentage of breast cancers.
BRCA gene pathogenic variants have a high lifetime risk of developing
breast and ovarian cancer and male carriers have an increased risk of
prostate and breast cancer. BRCA1 and BRCA2
Patients with a significant family history of breast cancer should be
Pathogenic variants in the BRCA1 and BRCA2 genes account for
referred to their local cancer genetics service for a formal cancer genetics
the majority of families with an apparently dominant-looking
risk assessment, discussion of risk management options such as surveil-
predisposition to breast cancer. However, they are only respon-
lance and risk-reducing surgery and consideration of genetic testing. If
sible for about 2% of all breast cancers.
a BRCA pathogenic variant is identified in a family, predictive testing
The BRCA1 and BRCA2 genes are tumour suppressor genes
can be offered to unaffected family members to clarify risks and help
and their proteins are involved in fundamental cell processes,
with risk management decisions.
including repair of DNA double-strand breaks and checkpoint
Patients with cancer are increasingly likely to have tailored treatment,
control of the cell cycle.
based on genetic information. Targeted therapies exploiting vulnerabil-
The role of tumour suppressor genes in cancer development
ities associated with deficient BRCA function are being developed.
can be explained by the ‘two-hit hypothesis’ proposed by Alfred
Knudson. In the case of BRCA1 or BRCA2, a breast cancer
Keywords Autosomal dominant; breast cancer; cancer genetics; genetic develops if both copies of the relevant gene in a single cell are
testing; germline mutation; magnetic resonance imaging; mammography;
damaged. Although the DNA in our tissues acquires somatic
ovarian cancer; pathogenic variants; risk assessment; screening; somatic
mutations over time, in most cases it is still likely to take many
mutation; tumour suppressor gene
years for both copies of a BRCA gene to become mutated in any
one cell. However, if a person inherits a germline pathogenic
variant in a BRCA gene from one parent, any cell subsequently
only requires a single somatic mutation to inactivate the second
Background copy of the gene. This explains why hereditary cancers often
develop at an earlier age than sporadic ones.
Breast cancer is the commonest cancer affecting women. A
Variation in the sequence of the BRCA genes is common.
woman in the developed world has a lifetime risk of developing
Some variation has no effect on protein function and therefore no
breast cancer of approximately 9e11%. In 2009, over 48,000
increase in cancer risk. Some variants interfere with protein
women in the UK were diagnosed with breast cancer. Each year,
function and lead to an increased risk of cancer. Such a change is
about 350 men are also diagnosed with breast cancer.
often loosely referred to as a ‘mutation’. However, some biolo-
The risk of developing breast cancer for women in the general
gists define a mutation as simply a change in DNA sequence,
population increases with age. Other factors known to increase
while others consider a mutation to be a sequence change
the risk include the use of hormone replacement therapy (HRT),
occurring below a certain frequency in a population or
especially combined oestrogen and progesterone preparations,
a sequence change associated with disease. To prevent this
hormonal contraceptives, obesity and alcohol. High parity,
confusion the term variant is preferred and variants are classified
young age at first childbirth, breastfeeding, late menarche and
as pathogenic, non-pathogenic or of unknown significance,
early menopause all decrease the risk.
depending on their associated cancer risk.
The BRCA1 gene is a large gene of 24 exons, located on the
long arm of chromosome 17. Pathogenic variants can be found in
Alexandra J Murray FRCP is a Consultant Clinical Geneticist at the any part of the gene and most result in truncation or total loss of
University Hospital of Wales, Cardiff and Singleton Hospital, Swansea, the BRCA1 protein. There is a wide spectrum of pathogenic
UK. Conflicts of interest: none declared. variants but there are a few common, ‘founder’ pathogenic
variants in certain populations such as Ashkenazi Jews. The
D Mark Davies MRCP PhD is a Clinical Lecturer in Cancer Genetics and commonest of these, 185delAG, is responsible for about one in
Medical Oncology at the University Hospital of Wales, Cardiff, UK. five cases of early onset breast cancer in Ashkenazi Jewish
Conflicts of interest: none declared. women. The BRCA2 gene has 27 exons and is found on the long

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 BASIC SCIENCE

 one first-degree relative with breast cancer diagnosed

Syndromes which predispose to breast cancer before age 40
 two first- or second-degree relatives with breast cancer
Syndrome Causative Main associated cancers
diagnosed before age 60
gene
 three or more first- or second-degree relatives with breast
cancer at any age
Hereditary breast BRCA1 Breast, ovarian
 a close relative with bilateral breast cancer
and ovarian BRCA2 Breast, ovarian, prostate, melanoma,
 a close male relative with breast cancer
cancer sarcoma, pancreatic
 a close relative affected by breast and ovarian cancer.
LieFraumeni TP53 Breast, soft tissue sarcoma,
Most referral guidelines, such as those above, assume the person
osteosarcoma, brain, leukaemia,
being referred is not themselves affected by a relevant cancer. An
adrenocortical carcinoma
easy way to adapt such guidelines for a person who has been
Cowden PTEN Breast, endometrial, thyroid
affected by cancer is to imagine that person has a twin sister and
Peutz Jeghers LKB1 Breast, pancreatic, gastrointestinal,
ask whether that twin sister warrants referral.
lung
If the family history is complex and involves other types of
Table 1 cancer such as ovarian cancer, prostate cancer, sarcoma, glioma
or adrenocortical carcinoma, it is best to refer to the local
arm of chromosome 13. As with BRCA1, pathogenic variants can guidelines or contact the regional genetics service directly.
occur throughout the gene and there are founder pathogenic
variants in some populations including the 6174delT mutation in Risk assessment
Ashkenazi Jews.
On receipt of a referral, the genetics team will gather detailed
information about the family history and draw up a family tree or
Cancer risks
pedigree. In many cases this will involve confirming diagnoses
Pathogenic variants in these genes show incomplete penetrance by reviewing medical records, pathology reports and cancer
(i.e. some people who carry a pathogenic variant will not develop registry records. The next step is a formal risk assessment, often
cancer). Pathogenic variants in the BRCA1 gene are particularly facilitated by the use of computer programmes that estimate
associated with an increased risk of early onset breast cancer, either the BRCA1/BRCA2 pathogenic variant carrier probabilities
ovarian cancer and fallopian tube cancer. The lifetime risks of or breast/ovarian cancer risks, such as BOADICEA.2
developing breast and ovarian cancer for a woman with a BRCA1 Patients will be assigned to one of three risk categories for
pathogenic variant are usually quoted as about 85% and 40% breast cancer:
respectively. The risks for a woman with BRCA2 pathogenic  Women at or near population risk of developing breast
variants may be a little lower, particularly the ovarian cancer cancer (i.e. a 10-year risk of less than 3% for women aged
risk, which is probably less than 20%. Pathogenic variants in 40e49 years and a lifetime risk of less than 17%) e these
BRCA2 are also associated with pancreatic cancer, sarcoma and women can be managed in primary care and do not require
malignant melanoma. Male carriers of BRCA pathogenic variants any additional screening other than that offered to all
have an increased risk of prostate cancer, and those with BRCA2 women i.e. 3-yearly mammograms from about the age of
pathogenic variants also have a significantly increased lifetime 50 through the NHS breast screening programme.
risk of developing breast cancer of about 6%.  Women at raised risk of developing breast cancer (i.e. a 10-
The breast cancers associated with BRCA1 tend to be high- year risk of 3e8% for women aged 40e49 years or a life-
grade, triple-negative (oestrogen receptor (ER)-, progesterone time risk of 17% but <30%) e these women may not be
receptor (PR)- and human epidermal growth factor receptor 2 seen in their local genetics clinic but will be offered
(HER2)-negative) tumours. The pathological spectrum of BRCA2 screening in secondary care or as part of a regional or
breast cancers is broadly similar to those of non-carriers. national screening programme for women with a family
history of breast cancer.
Management  Women at high risk of developing breast cancer (i.e. a 10-
year risk of >8% for women aged 40e49 years or a lifetime
The first step in managing a person who is concerned about her
risk of 30% or a 20% chance of a BRCA1, BRCA2 or
risk of developing breast cancer is to take a family history.
TP53 pathogenic variant in the family) e these women
Although it is important to ask about both the maternal and
should be seen in their local genetics clinic for discussion
paternal relatives, each side of the family should be considered
about screening programmes and, where appropriate,
separately. Not everyone with a family history of breast cancer
genetic testing and risk-reducing surgery.
will have an increased risk of developing the disease. Where
appropriate, referral can be made to their local regional genetics
Breast screening
service for risk assessment, counselling, advice about screening
programmes and sometimes genetic testing. Many regional Breast cancer screening for women with a family history should
genetics services have local referral guidelines that help to be offered in accordance with the NICE guidelines on familial
identify who should be referred. Although there may be some breast cancer.3 Women in the raised risk group or higher should
regional variations, it is reasonable to consider making a referral be offered annual mammographic surveillance from age 40 years
if a person has: and then 3-yearly screening from 50 years. Annual MRI

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 BASIC SCIENCE

surveillance should be offered to women aged 30e49 years who appears that the use of HRT does not reverse the reduction in
are known to have a BRCA1 or BRCA2 pathogenic variant and breast cancer risk in these women. The effectiveness of screening
women aged 20 years or older who are TP53 pathogenic variant for ovarian cancer remains unproven.
carriers (i.e. LieFraumeni syndrome). MRI surveillance is also
indicated in certain other high-risk situations which are detailed Medical management of affected BRCA pathogenic variant
in the NICE guidance. carriers
The BRCA status of women affected by cancer is increasingly
Genetic testing
impacting on how they are treated.5 Female pathogenic variant
When the family history is suggestive of a BRCA pathogenic carriers who have had breast cancer, have a significantly higher
variant, genetic testing can be undertaken. Ideally, this is per- risk of developing a second breast cancer in the contralateral
formed on DNA extracted from a blood sample of a family breast (approximately 25% compared to 10% in non-carriers).
member affected by a BRCA related cancer. The clues in the This raises the question whether a risk-reducing contralateral
family history that are suggestive of a pathogenic variant include: mastectomy should be performed, possibly as part of the initial
 multiple individuals on one side of the family with breast surgical procedure. There is no evidence that BRCA pathogenic
or ovarian cancer variant carriers are more radiosensitive than the general pop-
 a young average age of diagnosis ulation, in terms of response or toxicity. There is pre-clinical
 male breast cancer evidence that BRCA associated tumours may be more sensitive
 associated cancers (e.g. prostrate cancer, sarcoma, to certain chemotherapy drugs and this is currently being tested
pancreatic cancer) in large scale clinical trials.
 individuals with more than one primary cancer, including Advances in the understanding of the biological function of
bilateral breast cancer BRCA 1/2 encoded proteins have led to the development of tar-
 Ashkenazi Jewish ancestry. geted therapies, which are currently in clinical trials.6 The
In most laboratories both genes will be sequenced to identify BRCA1 and BRCA2 proteins are involved in DNA repair. The
point mutations or small deletions, and MLPA (Multiplex poly(ADP-ribose) polymerase (PARP) proteins also have impor-
Ligation-dependent Probe Amplification) will be performed to tant roles in DNA repair. Inhibiting PARP in the presence BRCA
look for deletions or duplications of one or more whole exons. deficiency leads to cell death but PARP inhibition in cells with
If a pathogenic variant is identified in either gene, unaffected, at- normal BRCA function is well tolerated. The concept that the
risk family members can be offered predictive testing to clarify their mutation or inhibition of two pathways can lead to cell death,
risks. Predictive testing should only be undertaken in regional when mutation or inhibition of either alone would not, is termed
genetics centres with appropriate pre-test and post-test counselling. synthetic lethality. PARP inhibitors have been tested in clinical
trials in patients with BRCA-related cancers and have shown very
Risk-reducing surgery in unaffected BRCA pathogenic variant encouraging results in phase 1 and II trials. However, the results
carriers of larger phase III studies have been mixed and considerable
Some women at high risk of breast or ovarian cancer want to be
work remains to define the role of PARP inhibitors. A
more proactive in managing their risk and request risk-reducing
surgery as an alternative to regular surveillance. The two options
available to these women are mastectomy and bilateral salpingo- REFERENCES
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SURGERY 31:1 3 Ó 2013 Elsevier Ltd. All rights reserved.