Neuro-Oncology Practice Advance Access published October 31, 2015

Neuro-Oncology Practice
Neuro-Oncology Practice 2015; 0, 1 – 12, doi:10.1093/nop/npv051

Genetic counseling and tumor predisposition in neuro-oncology practice

Erin M. Dunbar, Amanda Eppolito, and John W. Henson

Piedmont Brain Tumor Center, Piedmont Oncology, Atlanta, Georgia (E.M.D.); Genetic Counseling Service, Piedmont Oncology, Atlanta,
Georgia (A.E.); Piedmont Brain Tumor Center, Piedmont Oncology, Atlanta, Georgia (J.W.H.)

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Corresponding Author: John W. Henson, MD, Piedmont Oncology, 1800 Howell Mill Road, Suite 625, Atlanta, GA 30318 ([email protected]).

Tumor predisposition syndromes may be under-recognized in neuro-oncology practice. Identifying patients with a hereditary tumor
predisposition permits appropriate tumor management as well as surveillance and risk-reduction measures for patients and their families.
The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recently published referral guide-
lines for tumor predisposition assessment, providing an impetus to review the use of genetic counseling in neuro-oncology and to describe
features of the less stereotypic conditions from the perspective of neuro-oncology practice. This review also provides a framework for the
identification and management of these conditions, as well as references to guidelines and resources for providers and patients.

Keywords: brain tumor, familial, genetic, genetic counseling, hereditary.

Brain tumors are seen in numerous cancer susceptibility syn- neurofibromatosis type 1), while others require additional inqui-
dromes and approximately 5% of gliomas occur with familial fea- ry and examination (eg, polyposis prompting evaluation for fa-
tures,1 suggesting that tumor predisposition syndromes are often milial adenomatous polyposis). Therefore, evaluation for a
under-recognized in neuro-oncology practice. Identification of nervous system tumor predisposition syndrome requires not
patients with a hereditary tumor predisposition is critical to only a thorough review of a patient’s past medical and family
allow for surveillance and risk-reduction measures for other history, but also a targeted review of systems and physical ex-
health risks associated with the syndrome. As with the patient amination for features associated with these syndromes.
whose dysplastic gangliocytoma of the cerebellum leads to a Table 3 includes examples of physical manifestations of CNS
diagnosis of Cowden syndrome and identification of the heritable tumor predisposition syndromes.
risk of multiple systemic cancers, awareness of these syndromes The patient’s family history should include at least first-degree
can result in life-saving measures for the patient and their family (parents, children, and full siblings) and second-degree relatives
members. In addition, there is potential impact on treatment de- (aunts/uncles, grandparents, half-siblings, grandchildren, and
cisions and prognosis. nieces/nephews) on both sides of the family (paternal and mater-
The American College of Medical Genetics and Genomics and nal). For affected family members the following should be docu-
the National Society of Genetic Counselors recently published re- mented: type(s) of primary cancer, age at diagnosis, relationship
ferral guidelines for tumor predisposition assessment,2 providing to patient, and lineage (maternal or paternal). Patients should
an impetus to review the use of genetic counseling in neuro- also be asked about any known tumor susceptibility in the family,
oncology and to describe features of the less stereotypic condi- any prior genetic testing in the family, and family ethnicity. The
tions from the perspective of neuro-oncology practice. This review presence of consanguinity should be also noted to evaluate the
also provides a framework for the identification and manage- risk of an autosomal recessive syndrome. The American Society
ment of these conditions, as well as reference and resources for of Clinical Oncology recommends obtaining a family history at
providers and patients. the patient’s initial oncology visit and updating the family history
if new family members are diagnosed or more family history in-
formation becomes available.3 A sample questionnaire is provid-
Red Flags Suggesting Tumor Predisposition ed as supplemental material.
Syndromes
Several red flags in a patient’s personal and family history should Role of Genetic Counselors and Medical
prompt consideration of a hereditary tumor predisposition syn-
Geneticists
drome (Table 1).
Features associated with some tumor predisposition syn- Genetic counselors are health care providers with training in ge-
dromes can be fairly obvious (eg, café au lait macules in netics and counseling skills, typically at the master’s level. Genetic

Received 31 July 2015

# The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.
For permissions, please e-mail: [email protected].

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Dunbar et al.: Genetic counseling and tumor predisposition

Table 1. Red flags for hereditary cancer well as potential implications for the patient and family; discuss
genetic testing options; provide psychosocial support; and coordi-
Patient nate genetic testing, if indicated and desired. Discussion about
(a) Multiple primary tumors in the same organ, paired organs, different genetic testing includes the benefits, risks, and limitations of test-
organs, or multifocality in one organ ing, as well as insurance and privacy issues. The patient is thus
(b) Younger age at tumor diagnosis able to make an informed decision about whether to pursue ge-
(c) Rare histology netic testing.
(d) Rare for sex When genetic testing is performed, the genetic counselor
(e) Associated genetic traits, congenital defects, or other rare disease communicates the results to the patient and the referring provid-
(f) Presence of cutaneous lesions er. He or she also reviews with the patient associated risks of any

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Family identified genetic variation as well as management recommen-
(a) First-degree relative with the same or a related tumor, or tumor dations and implications for family members. Genetic counselors
belonging to a known syndrome often help coordinate genetic testing for at-risk family members
(b) Two or more first-degree relatives with rare tumors to help guide their medical management. They can also review
(c) Three or more relatives in two generations with tumors of the same reproductive options available to patients to help reduce the
or related sites risk of syndrome transmission (such as preimplantation genetic
diagnosis, egg/sperm donation, or prenatal testing) if a patient
desires.
counselors have expertise in evaluating and counseling patients
for hereditary syndromes, as well as coordinating and interpreting
genetic testing. Over the past decade, the number of genetic Genetic Testing
counselors at cancer centers has grown and genetic counselors Genetic testing should be offered when a patient’s personal and/
are now employed at many larger academic, community, and or family history is suggestive of a hereditary syndrome, the ge-
public hospitals. Advanced practice genetics nurses are also em- netic test can be adequately interpreted, and the results will af-
ployed at some cancer centers. fect the medical management of the patient or their family.6
Medical geneticists are physicians trained to evaluate patients Genetic testing is usually most informative when first performed
for genetic syndromes through medical and family history (often in an affected family member, or the family member with the
performed by a genetic counselor working with the geneticist), re- highest clinical suspicion of the syndrome, rather than on a family
view of systems, and detailed physical examination. Referral to a member with no clinical manifestations.
medical geneticist is most strongly indicated for evaluation of Genetic testing comes in many forms. Germline testing for
syndromes with dermatologic manifestations or other findings constitutional gene mutations is usually performed on DNA ob-
that require physical examination, such as neurofibromatosis tained from a peripheral blood sample, although buccal samples
type 1 or tuberous sclerosis. In some cases, medical geneticists are available more recently. If a patient has had a recent blood
can provide a clinical diagnosis of a tumor predisposition syn- transfusion, germline testing may need to be delayed to allow
drome when genetic testing is not available or has incomplete for heterologous mixtures to resolve over 2 to 4 weeks. In patients
detection. Medical geneticists can also aid in the management who have undergone allogeneic stem cell transplant, germline
of patients with tumor predisposition syndromes and are most testing is usually performed on fibroblasts instead.
often employed at academic institutions. For most syndromes, full gene sequencing and deletion/dupli-
If a tumor predisposition syndrome is suspected in a neuro- cation testing is recommended. Table 2 gives an overview of the
oncology clinic, referral to a trained genetics provider should be genes and testing details for these susceptibility syndromes. Gene
initiated. Referral documents including relevant medical re- sequencing helps detect smaller gene mutations (eg, point muta-
cords/pathology reports, and family history information should tions and small insertions/deletions), while deletion/duplication
be provided. A searchable list of genetics providers (by specialty analysis helps detect larger alterations. These techniques can
and location) is available from the National Society of Genetic be performed sequentially (usually sequencing with reflex to
Counselors and the American College of Medical Genetics and deletion/duplication) or concurrently. Mutation detection rates
Genomics (see Table 4). When genetic counseling by a qualified of each technology vary based on the gene and the types of mu-
provider is not performed, unnecessary tests may be ordered, in- tations commonly associated with that syndrome. If there is a
correct interpretation of test results may occur, and inappropriate known mutation detected in a family, then targeted testing for
medical management may be performed.4 Therefore, genetic the familial mutation is usually recommended.
testing should be performed in the context of pre-test and post- Tumor specimens may also be analyzed as part of a workup for
test counseling by a specialized health care provider.5 inherited syndromes. In some cases, especially in syndromes with
a high rate of somatic mosaicism (eg neurofibromatosis type 2),
genetic testing on tumor tissue may help detect a causative mu-
Genetic Counseling Process
tation when germline testing on blood or buccal sample cannot.
During a typical initial genetic counseling visit, the genetic coun- In addition, tumor immunohistochemistry can help screen for in-
selor will elicit a detailed medical history and three-generation dividuals likely to have a genetic syndrome and help direct which
family history (including third-degree relatives); assess the risk gene to test in the germline, as in the case of CMRD/Lynch syn-
for one or more tumor predisposition syndrome(s); discuss the drome where immunohistochemistry can identify loss of one or
natural history and inheritance of the suspected syndrome(s) as two of four mismatch repair proteins.

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Table 2. Genetic features of tumor predisposition syndromes in neuro-oncology

Syndrome Gene and Molecular Features Testing

Less Commonly Recognized Syndromes

Carney complex PRKAR1A. Protein kinase A. Cell-signaling oncogene. SEQ/DD (70% DR). If negative, gene panel or
Autosomal dominant. Constitutional inactivating point genomic testing may be considered.
mutation followed by LOH.
Constitutional mismatch repair MMR genes MLH1, MSH2, MSH6, PMS2. Constitutional IHC tumor for MMR proteins to identify causative
deficiency mutation in both alleles. PMS2 60% of cases. MSI and gene. MSI testing. SEQ/DD of MMR genes to detect

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NF1 result from mutator phenotype. two pathogenic mutations in the same gene.
Lynch syndrome MMR genes MLH1, MSH2, MSH6, PMS2, EPCAM. Initial tumor screening with MSI and/or IHC for MMR
Constitutional mutation in one allele with somatic proteins can help target which MMR gene(s) to
inactivation of the second allele. test, but most reliable in colorectal and
endometrial tumors. SEQ/DD of MMR genes.
EPCAM DD only. DR varies depending on phenotype
and testing performed.
Cowden syndrome PTEN. Phosphatase activates PI3K/Akt signaling, tumor SEQ (including promoter region)/DD of PTEN (DR
suppressor. Constitutional mutation in coding or 25%–80%). If negative, testing of other genes
promoter regions. Second allele through multiple with overlapping presentation may be considered.
mechanisms.
Familial adenomatous APC. APC large, multifunctional protein active in Wnt- SEQ/DD of APC gene (,100% DR in classic FAP
polyposis syndrome (FAP) signaling among others. Wide variety of mutation types. phenotype; ,30% DR in attenuated FAP
Strong genotype-phenotype correlation. phenotype). Depending on polyp history, testing of
other polyposis genes (eg, MUTYH) should be
considered.
Li-Fraumeni syndrome TP53. P53 is “guardian of the genome.” Constitutional SEQ/DD of TP53 (80% DR).
point mutations in hot spots.
Melanoma-astrocytoma CDKN2A, CDKN2B, p14/ARF. Tumor suppressors involved in SEQ/DD of CDKN2A (p16 and p14ARF). Consider CDK4
syndrome p53 and Rb pathways. Constitutional deletion of one SEQ (,50% DR in familial melanoma).
allele.
Nevoid basal cell carcinoma PTCH1. Patched-1 is a receptor for sonic hedgehog among SEQ/DD of PTCH1 (50 –85% DR). Consider tumor
syndrome others. Microdeletions are common. testing (usually on basal cell carcinoma ) if
mosaicism suspected.
Stereotypic Tumor Predisposition Syndromes
Neurofibromatosis type 1 NF1. Neurofibromin, activator of Ras GTPase. Wide range of SEQ (mRNA and genomic DNA)/DD of NF1 (95%
mutation types. DR). Depending on phenotype, may consider
SPRED1 or other gene analysis.
Neurofibromatosis type 2 NF2. Merlin protein may coordinate growth-factor signaling SEQ/DD of NF2 (72% DR in simplex cases; .92% DR in
and cell adhesion. Wide range of mutation types. familial cases). Consider tumor testing in simplex
cases.
Tuberous sclerosis TSC1 (hamartin) mutant in one-third of cases, TSC2 SEQ/DD of TSC1 and TSC2 (85% DR). Consider tumor
(tuberin) mutant in two-thirds of cases. Heterodimers, testing when somatic mosaicism is suspected.
regulators of AKT pathway. Point mutations common.
von Hippel-Lindau syndrome VHL. pVHL involved in hypoxia response. Wide variety of SEQ/DD of VHL (.99% DR).
mutation types with deletions being most common.

Abbreviations: DD, deletion and duplication analysis; DR, detection rate; IHC, immunohistochemistry; LOH, loss of heterozygosity; MMR, mismatch repair;
MSI, microsatellite instability; NF1, neurofibromatosis type 1; SEQ, sequencing analysis; Rb: retinoblastoma.

More recently, next-generation sequencing has become clini- and syndromes are being considered in the differential. Next
cally available and has broadened options for genetic testing. generation gene panels are identifying a higher proportion of he-
Using next-generation sequencing, multiple tumor predisposition reditary predisposition in patients with certain cancers compared
genes can be evaluated concurrently at prices comparable to with previous estimates. For example, approximately 10% of
analysis of 2 or a few genes by traditional Sanger sequencing. ovarian cancer was classically thought to be hereditary; however,
While there are limitations of next-generation sequencing,7 this gene panel testing now identifies a pathogenic mutation in 1 of
new technology can be more efficient and cost-effective com- 13 genes in almost 24% of unselected patients.8 Next-generation
pared with traditional sequential testing when multiple genes sequencing technology now also allows for whole genome or

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Dunbar et al.: Genetic counseling and tumor predisposition

exome sequencing in the oncology context, which, although not Genetic testing can be inconclusive if a genetic variant of un-
yet broadly used clinically, can result in new gene discovery. certain significance is detected. This occurs when a variation is
found in a gene, but it is not currently known whether this varia-
tion is pathogenic (causes the hereditary syndrome), or whether it
Practical Considerations for Genetic Testing is a polymorphism (a normal variation in the gene with no health
effects). As additional data become available, these uncertain
Timing of genetic testing depends on the syndrome, as well as
variants may be reclassified, but in many cases this can take sev-
patient and family preference. In general, predictive genetic
eral years.
testing for syndromes with adult-onset should be performed
Genetic testing is complicated by underlying genetic charac-
when an individual is 18 or older and can make an informed de-
teristics. For example, the presence of PMS2 pseudogenes (non-
cision about testing and when testing results are obtained. Test-

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functional copies of genes) can make it difficult to know if
ing should be considered at or before the age when initiation of
detected gene mutations may be present in the actual PMS2
surveillance is recommended if an individual were to test posi-
gene or the pseudogene. In addition, several tumor predisposition
tive. For example, individuals with Lynch syndrome are recom-
syndromes can be the result of de novo mutations, especially if
mended to begin colonoscopies around age 20 – 25, so gene
the gene, like NF1, is susceptible. Although detection varies
testing for asymptomatic family members should be considered
based on the testing technology used, low-level mosaicism for
around age 20. The American College of Medical Genetics and
a gene mutation may be missed. If present in the gonadal tissue,
Genomics now recognizes that there may be cases when, after
these missed mutations can still be passed on to offspring. When
thorough counseling with the family, testing may be performed
mosaicism is detected, it is currently difficult to predict the muta-
under age 18 for adult-onset conditions.9 For syndromes with
tion burden in each tissue type.
potential manifestations in childhood (eg, Li-Fraumeni syn-
drome, Cowden syndrome, familial adenomatous polyposis
syndrome, and others), testing during childhood is appropriate
if desired by the family to help better guide the child’s medical Less Commonly Recognized Tumor
management. The prenatal identification of macrocephaly can Predisposition Syndromes
be important in management (Cowden and nevoid basal cell
carcinoma syndromes). Carney Complex
Single-gene testing can cost around $1500, but cost varies Tumors
based on the testing lab and the size of the gene. Insurance cov-
erage for genetic testing varies based on the test being per- In the neuro-oncology clinic a diagnosis of melanotic schwan-
formed, insurance carrier, and patient history. When the noma, particularly of the psammomatous melanotic schwan-
patient’s personal and/or family history is suggestive of a partic- noma (PMS) subtype, should prompt consideration of this
ular syndrome and testing could affect the patient’s medical syndrome. Systemic lesions seen in Carney Complex are listed in
management, genetic testing coverage can be obtained in Table 3.
most cases. PMS, a subtype of melanotic schwannomas, occurs in up to
Genetic testing also has the potential to raise legal, ethical, 8% of patients with Carney Complex and are usually found as sin-
and psychosocial issues, including nonpaternity, discordant gle lesions along the proximal peripheral nerve roots in the spinal
views about genetic information among family members, and canal and paraspinal regions. Melanotic schwannomas associated
anxiety. Concern about the potential for genetic discrimination with Carney Complex typically occur one decade (age 20) earlier
can be a barrier to family members undergoing genetic testing. compared to sporadic examples. Histopathological differentiation
The Genetic Information Nondiscrimination Act (GINA) was from melanoma can be difficult. Aggressive behavior with distant
signed into law in 2008 and prohibits discrimination in health in- metastasis had been reported in up to 20% of cases.
surance coverage and employment based on family history or ge-
netic testing information. GINA still has some limitations,
including the fact that it does not apply to individuals who have Molecular Genetics
manifested disease.
The PRKAR1A gene encodes the type 1A regulatory subunit of pro-
tein kinase A.10 Constitutional inactivating point mutations and
loss of heterozygosity (LOH) through allelic deletion are detected
Pitfalls in Genetic Testing
in 70% of patients with Carney Complex, and mutations are scat-
There are significant potential pitfalls in genetic testing. Mutation tered across the coding region of the gene in different families.11
detection rates are never 100%; therefore negative genetic test- A subset of cases is associated with an unknown gene at 2p16.
ing usually does not completely rule out the associated syn- The expression pattern is autosomal dominant with 100%
drome. A negative genetic test may be the result of a mutation penetrance. One third of cases are from de novo mutations.
not detectable by the technology performed, a mutation in a dif- Genotype-phenotype correlations are not known to be relevant
ferent causative gene, mosaicism, or the patient may not have to patients with PMS, although those melanotic schwannomas
the associated syndrome. As new genes are found to be associ- containing multiple genetic changes are likely to also have inac-
ated with a particular syndrome (eg PMS2 and EPCAM added as tivation of the nearby TP53 gene. Sporadic melanotic schwanno-
Lynch syndrome genes), detection rates go up and patients mas (eg epithelioid and spindle cell) may be seen in the absence
may need additional testing as genetics knowledge and testing of Carney Complex, and these tumors harbor the same mutations
technologies improve. isolated to tumor cells.12

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Table 3. Situations that merit referral for a possible tumor predisposition syndrome

Less Commonly Recognized Syndromes by Tumor Presentation

Situation raising suspicion Syndrome to consider Associated systemic tumors Other associated clinical features Incidence, average age,
de novo ratea
Surveillance

Psammomatous melanotic Carney Complex (CNC) PMS; atypical Cushing’s syndrome Lentiginous cutaneous lesions with typical PMS in 8% of CNC cases
schwannoma (PMS) (including primary pigmented nodular distribution (lips, conjunctiva, and inner Age 20 y
adrenocortical disease and or outer canthi, vaginal or penile 33% de novo
growth-hormone secreting pituitary mucosa, manifesting from birth through Surveillance guidelines
adenomas [acromegaly]); pancreatic puberty), blue nevi (face, trunk, lips, and have been
cancer; thyroid adenomas (especially in sclera) published35
a young patient) and carcinomas;
Sertoli cell cancer of the testicle;
ovarian cysts; myxomas (cutaneous
or mucosal, atrial myxoma,
osteochondralmyxoma); breast ductal
adenomas
Brain tumor diagnosis at age ,18 if Constitutional mismatch Colorectal adenocarcinoma; endometrial Autosomal recessive inheritance, NF1-like Age 9 y
any of the following criteria are repair deficiency adenocarcinoma; carcinoma of the findings, especially café au lait macules De novo rare
met: stomach, ovaries, small bowel, biliary but also axillary/inguinal freckling, Lisch Surveillance guidelines
(a) Signs of NF1 tract, and/or pancreas; urothelial nodules, neurofibromas, or tibial have been
(b) Consanguineous parents carcinoma as with Lynch but younger pseudoarthosis published36

Dunbar et al.: Genetic counseling and tumor predisposition

(c) Family history of Lynch onset; hematologic malignancies;
syndrome-associated cancer embryonic tumors
(d) Second primary cancer
(e) Sibling with a childhood cancer
Brain tumor and 2 additional cases of Lynch syndrome Colorectal adenocarcinoma; endometrial Sebaceous gland tumors GBM in 1 –3% of Lynch
any Lynch syndrome-associated adenocarcinoma; carcinoma of the syndrome cases
tumors in the same person or in stomach, ovaries, small bowel, biliary Age 50 y
relatives tract, and/or pancreas; urothelial De novo rare, but
carcinoma incomplete
penetrance can
result in negative
family history
Surveillance guidelines
have been
published34

Continued
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 Table 3. Continued
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Dunbar et al.: Genetic counseling and tumor predisposition

Less Commonly Recognized Syndromes by Tumor Presentation

Situation raising suspicion Syndrome to consider Associated systemic tumors Other associated clinical features Incidence, average age,
de novo ratea
Surveillance

Dysplastic gangliocytoma of the Cowden syndrome Breast cancer; thyroid cancer (especially Macrocephaly, pigmentation of the glans LD 15% in Cowden
cerebellum (Adult follicular); endometrial cancer; penis, mucocutaneous lesions syndrome
Lhermitte-Duclos syndrome) gastrointestinal hamartomas (including (trichilemmomas, acral keratosis, Wide age range
ganglioneuromas); renal cell cancer; mucocutaneous neuromas, oral .50% de novo
colon cancer; thyroid structural lesions papillomas), autism spectrum disorder, Surveillance guidelines
intellectual disability, esophageal have been
glycogenic acanthosis, lipomas, published37
testicular lipomatosis, vascular
anomalies
Medulloblastoma and ≥10 Familial adenomatous Colorectal cancer (and polyposis); Congenital hypertrophy of the retinal Medulloblastoma in 1%
cumulative adenomatous colon polyposis (FAP) duodenal cancer (and polyps); fundic pigment epithelium, dental of FAP cases
polyps in the same person gland polyps (and gastric cancer); abnormalities, osteomas, soft tissue 18 y
hepatoblastoma; thyroid cancer; tumors, adrenal masses 20% de novo
pancreatic cancer; bile duct cancer; Surveillance guidelines
desmoid tumors have been
published34
Brain tumor and 1 additional Li-Fraumeni syndrome Soft tissue sarcoma; osteosarcoma; early CNS tumor in 20 –60%
Li-Fraumeni syndrome tumor in the (LFS) onset breast cancer; adrenocortical of LFS cass
same person or in 2 relatives, one tumor; leukemia; bronchoalveolar Bimodal age
at age ≤45 y cancer; colorectal cancer; other cancers distribution
also reported 20% de novo
Surveillance guidelines
have been
published5
Astrocytoma and melanoma in the Melanoma-astrocytoma Melanoma; astrocytoma Wide age range
same person or in 2 first-degree syndrome Surveillance guidelines
relatives have not been
published, consult
appropriate
specialists
Medulloblastoma Diagnosed at age Nevoid basal cell Basal cell carcinomas (especially in young Lamellar calcification of the falx (younger 5% risk
,18 and one additional nevoid carcinoma syndrome patients or those with multiple basal than age 20), mandibular keratocyst, medulloblastoma
Neuro-Oncology Practice

basal cell carcinoma syndrome cell carcinomas) ovarian fibromas, cardiac fibromas, 2y
criterion in the same person palmar or plantar pits, 20% de novo
lymphomesenteric or pleural cysts, Surveillance guidelines
macrocephaly, cleft lip/palate, vertebral have been
anomalies, polydactyly, ocular published23
anomalies

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 Table 3. Continued
Neuro-Oncology Practice

Stereotypic Tumor Predisposition Syndromes

Situation raising suspicion Syndrome to consider Associated systemic tumors Other associated clinical features Incidence, average age,
de novo ratea
Surveillance

Bilateral optic nerve gliomas (ONG), NF1 Neurofibromas; malignant peripheral Café au lait macules, axillary or inguinal ONG in 20% of NF1
diffuse astrocytoma nerve sheath tumors; leukemia; freckling, Lisch nodules, osseous lesions, cases
gastrointestinal stromal tumor; breast learning disabilities, autism spectrum, Age 6 y
cancer others 50% de novo
Surveillance guidelines
have been
published27
Bilateral vestibular schwannoma NF2 Meningioma; ependymoma; schwannoma Cataract, lenticular opacities VS by age 30 y
of the spinal nerves; glioma; 50% de novo and these
neurofibroma cases are often
mosaic (ie unilateral
VS)
Surveillance guidelines
have been
published29
Subependymal giant cell Tuberous Sclerosis Renal angiomyolipoma; cardiac Facial angofibromas, forehead plaque, SEGA in 10% of TS
astrocytoma (SEGA) and one Complex (TSC) rhabdomyoma ungula or periungual fibroma, cases

Dunbar et al.: Genetic counseling and tumor predisposition

additional TSC criterion in the hypomelanotic macules, shagreen Childhood,
same person patch, cortical tuber in brain, 66% de novo
subependymal glial nodule, retinal Surveillance guidelines
hamartoma, lymphangiomyomatosis, have been
dental pits, rectal hamartomas, bone published30
cysts, confetti skin lesions, renal cysts,
cerebral white matter radial migration
lines, retinal achromic patch, gingival
fibromas
Hemangioblastoma, cerebellum, von-Hippel Lindau Renal cell carcinoma (clear cell); retinal Renal cysts, pancreatic lesions, epididymal 20% de novo
and rarely pituitary stalk syndrome angioma; pheochromocytoma, tumors, cystadenoma of the broad Surveillance guidelines
endolymphatic sac tumors ligament have been
published31
Adapted by permission from Macmillan Publishers Ltd: Genetics in Medicine2

a
Patients with de novo mutations will lack a family history of the associated syndrome.
Abbreviations: NF1, neurofibromatosis type 1; NF2, neurofibromatosis type 2; VS, vestibular schwannoma.
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Table 4. Additional resources

Resource Description URL

GeneReviews Summaries of many genetic conditions, including natural history, www.ncbi.nlm.nih.gov/books/NBK1116

genetic testing, and medical management
GeneTests Searchable site for genetic testing laboratories, clinics, and test www.genetests.org
availability by gene
Online Mendelian Inheritance Compilation of genes and genetic conditions www.ncbi.nlm.nih.gov/omim
in Man (OMIM)

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Patient Reading about General, lay information, including what to expect at a genetic www.cancer.net/navigating-cancer-care/
Genetics counseling visit and a cancer family history questionnaire cancer-basics/genetics
Familial Cancer Database Searchable database of features associated with tumor syndromes www.familialcancerdatabase.nl

Constitutional Mismatch Repair Deficiency Lynch Syndrome

Tumors Tumors
Gliomas and primitive neuroectodermal tumors occur in over Glioblastoma is the brain tumor associated with Lynch syndrome.
one-half of patients with constitutional mismatch repair defi- Lynch syndrome is the major cause of hereditary nonpolyposis
ciency (CMRD). Patients have features of NF1, but especially colorectal cancer.15,16 The most common systemic tumors aris-
café au lait spots and axillary freckling, often distributed in a seg- ing in these patients are listed in Table 3; however, a broad
mental, mosaic pattern. Other lesions seen in CMRD are listed in array of systemic tumors is seen in these patients.
Table 3. Glioblastoma is the most common brain tumor in these pa-
High-grade gliomas are the most common brain tumors in tients, occurring in 1% to 3% of patients with Lynch syndrome.
these patients; with glioblastoma and gliosarcoma the most Anaplastic astrocytoma, ganglioglioma, meningioma, and
often encountered lesions.13 Anaplastic astrocytomas, oligoden- hemangioblastoma have also been reported. Lynch syndrome is
drogliomas, and gliomatosis cerebri have been reported. Cerebral one cause of Turcot syndrome. Age of brain tumor diagnosis is
primitive neuroectodermal tumors and medulloblastomas are about 50 years, which is much older than the typical onset of co-
less common. Brain tumors are diagnosed very early, at an aver- lorectal tumors occurring in these patients, although some of the
age age of 9 years. Turcot syndrome, a term familiar to neuro- brain tumors have appeared at an early age, and some colorectal
oncologists, can result from CMRD, but can be seen in two distinct cancers can occur at later ages.
syndromes: CMRD/Lynch syndrome and familial adenomatous
polyposis syndrome (FAP; see below). Molecular Genetics
MMR genes underlie this syndrome and CMRD (above). There is an
Molecular Genetics inherited inactivating or truncating mutation of an allele of 1 of
MLH1, MSH2, MSH6, and PMS2 are four genes in the mismatch re- the 4 MMR genes followed by somatic inactivation of the second al-
pair molecular system (MMR) that are altered in the spectrum of lele. Alternatively, hypermethylation-dependent silencing of the
CMRD and the less severe Lynch syndrome (see below). MMR is a MSH2 gene promoter due to a 3′ deletion of the adjacent epithelial
cellular system that corrects DNA replication errors and DNA cell membrane (EPCAM) gene can cause Lynch syndrome. EPCAM
damage. CRMD is based on constitutional inactivation of both al- exhibits tissue-specific expression and is thus an example of a mech-
leles of 1 of the 4 mismatch repair genes and is associated with a anism for cell-specific tumor formation. Lynch syndrome has auto-
larger number of tumor types arising at an earlier age compared somal dominant expression with incomplete penetrance. De novo
with Lynch syndrome in which a single mutant allele is inherited. mutations are rare, but due to incomplete penetrance not all pa-
The CRMD mutations are compound heterozygous or homozy- tients have a family history of Lynch syndrome cancers. Associated
gous with one mutation from each parent, both of who usually tumors demonstrate microsatellite instability, as described above.
have Lynch syndrome, sometimes unrecognized, affecting the
same gene. CMRD has an autosomal recessive expression pattern Cowden Syndrome
with full penetrance. De novo mutations are rare. Brain tumors are
more common with MSH6 or PMS2 mutations. Tumor cell DNA Tumors
demonstrates microsatellite instability, in which short repetitive Dysplastic gangliocytoma of the cerebellum, also known as
intronic DNA sequences are shorter or longer than in normal Lhermitte-Duclos syndrome (LD), is highly suggestive of Cowden
cells from the same individual. Microsatellite instability is a fea- syndrome in adult onset cases.17 Childhood LD is usually not as-
ture of the mutator phenotype and is likely a direct result of sociated with Cowden syndrome. Tricholemmomas of the skin
MMR deficiency. Segmental NF1 features likely arise from postzy- and macrocephaly are common. Associated systemic tumors
gotic mutations of the mutation-susceptible NF1 gene. Loss of ex- are listed in Table 3.
pression of one of the MMR genes is seen in all grades of sporadic LD is a cerebellar mass lesion that replaces the granular-cell
astrocytomas, but microsatellite instability is seen in only 5% of layer and Purkinje cells of the cerebellum with excessive numbers
glioblastomas.14 of hypertrophic ganglion cells. This results in thickening of the

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 Dunbar et al.: Genetic counseling and tumor predisposition

cerebellar folia. No other nervous system tumors are known to be Cancers “classic” to LFS are detailed in Table 3, although others
associated. LD is seen in 15% of patients with Cowden syndrome may occur.
and comes to clinical attention across a wide range of ages. The CNS tumors associated with LFS include astrocytomas, glioblas-
lesions show slow, if any, detectable growth. tomas, medulloblastomas, neuroblastomas, and choroid plexus
carcinomas. The likelihood of germline TP53 pathogenic variants
Molecular Genetics in children with choroid plexus carcinoma is very high, even in
the absence of a family history of LFS.21 CNS tumors occur most
The PTEN gene creates a lipid and protein phosphatase that leads
commonly between birth to 10 years and after 20 years. CNS can-
to activation of the phosphoinositol-3-kinase (PI3K)/AKT path-
cer risk in families with LFS ranges from 20% to 60%.
way. Normal PTEN signaling leads to G1 cell-cycle arrest and ap-
optosis, and is thus a tumor suppressor gene. Mutations are

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detected in only 30% of patients; however, the majority of tumors Molecular Genetics
demonstrate loss of PTEN expression. Point mutations in the cod- TP53 is often referred to as “the guardian of the genome,” and fol-
ing regions and promoter are known, as are deletions and dupli- lowing loss of this tumor suppressor gene cells with DNA damage
cations. The second allele is inactivated through LOH, second fail to undergo DNA repair or apoptosis. Point mutations or small
point mutation, or epigenetic silencing. The inheritance pattern deletions affecting hot spots are the most common constitutional
is autosomal dominant. Only 10% to 50% of patients have an af- lesions, with subsequent LOH in the second allele occurring in tu-
fected parent, and thus many cases appear to be de novo. mors. The expression pattern is autosomal dominant. It is estimat-
Genotype-phenotype correlations have not been described for LD. ed that at least 70% of patients with a clinical diagnosis of LFS
have an identifiable germline pathogenic allelic variant in TP53.
Familial Adenomatous Polyposis Syndrome As many as 20% of cases have a de novo germline TP53 mutation.
Tumors Small minorities of patients with LFS-associated cancers have mu-
tations involving a different tumor suppressor gene, CHEK2. CNS tu-
The occurrence of medulloblastoma in a patient with familial ad- mors are more common when the TP53 pathogenic variant lies in
enomatous polyposis syndrome (FAP) represents one of the forms the loop that contacts the minor groove of DNA.
of Turcot syndrome (see CMRD/Lynch syndromes, above).18 Pa-
tients with classic FAP develop hundreds of colon polyps starting
in the middle of their teenage years, and without colectomy Melanoma-Astrocytoma Syndrome
develop colon cancer. Turcot syndrome and FAP represent 2 of Tumors
the 4 APC-associated precancerous polyposis conditions, each
A wide variety of neural tumors have been reported among
with overlapping clinical phenotypes, and with the other 2 con-
members of families with hereditary melanoma or pancreatic
sisting of attenuated FAP syndrome and Gardner syndrome. Sys-
cancer.22 A familial component may be seen in up to 10% of mel-
temic features are detailed in Table 3.
anoma patients.
Medulloblastomas occur in 1% of patients with FAP. Other
Astrocytomas of all grades, medulloblastoma, ependymoma,
brain tumors reported in patients with FAP include astrocytomas,
meningioma, and vestibular schwannoma have been seen in
ependymoma, pineoblastoma, and ganglioglioma.19 The average
these patients. Astrocytomas are the most common. These tu-
age at presentation is 18 years. Brain tumors may appear before
mors may be discovered before or after the melanoma. A wide
or after colon findings.
range of ages at diagnosis is seen, including many patients who
develop brain tumors after age 50 years.
Molecular Genetics
The APC gene encodes a large, multifunctional APC protein that has Molecular Genetics
roles in signal transduction in the Wnt-signaling pathway, intercel-
lular adhesion, cytoskeletal stability, and possibly regulation of the The CDKN2A (encoding the p16 protein), CDKN2B (p15 protein),
cell cycle and apoptosis. A wide variety of mutation types have and p14/ARF (p14 protein) genes at 9p21 underlie this syndrome.
been detected, ranging from deletions (common) of varying sizes These proteins act as tumor suppressor genes in the p53 and ret-
to point mutations. Remarkably, brain tumors are seen with distal inoblastoma pathways. Constitutional deletion of 1 allele of these
lesions in the APC gene, in particular with pathogenic variants in co- genes is the most common genetic abnormality. The expression
dons 457–1309. FAP is autosomal dominant in its expression and pattern is autosomal dominant. Inactivation of the p16 protein is
up to 20% of cases lack a family history, suggesting the common common in sporadic high-grade astrocytomas.
occurrence of de novo mutations. Although the diagnosis is made
primarily on clinical findings, testing of APC gene confirms the path- Nevoid Basal Cell Carcinoma Syndrome
ogenic variants in up to 90% of affected patients and is useful in
testing at-risk family members. Tumors
Medulloblastoma in association with multiple jaw keratocysts
Li-Fraumeni Syndrome and basal cell carcinomas should trigger consideration of nevoid
basal cell carcinoma syndrome, or Gorlin syndrome.23 This syn-
Tumors drome predisposes patients to cancerous and noncancerous tu-
Multiple types of brain tumors are seen with Li-Fraumeni syn- mors throughout the CNS and body, as detailed in Table 3.
drome (LFS). LFS patients have a greatly increased risk of many The most common brain tumor is medulloblastoma, although
types of cancer throughout the body, beginning in childhood.20 an association with meningioma and lymphoma has been

Neuro-Oncology Practice 9 of 12
Dunbar et al.: Genetic counseling and tumor predisposition

reported. The lifetime risk of a brain tumor is 5% and the peak age novo mutation rate approaches 50%. Many different types of mu-
of incidence is 2 years. Medulloblastomas associated with nevoid tations are known.
basal cell carcinoma syndrome are typically of the desmoplastic
subtype. Tuberous Sclerosis
Tumors
Molecular Genetics
Subependymal giant cell astrocytomas (SEGA) occur as unilateral
The PTCH1 tumor suppressor gene encodes the protein or bilateral tumors along the ependymal surface at the foramen
patched-1. Patched-1 is a receptor that interacts with various li- of Monroe.30 They are slowly growing tumors that produce risk of
gands, such as sonic hedgehog, to regulate cell proliferation. Con- obstructive hydrocephalus. The tubers of tuberous sclerosis are
stitutional mutation of the PTCH1 tumor suppressor gene is most

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hamartomas rather than neoplasms. Systemic features are de-
commonly the result of a microdeletion. Expression is autosomal tailed in Table 3.
dominant. De novo mutations in the PTCH1 gene occur in about
20% of cases.24
Molecular Genetics
TSC1 encodes the hamartin protein and TSC2 encodes the tuberin
Stereotypic Tumor Predisposition Syndromes protein. These proteins form heterodimers that regulate the AKT
These conditions are better known, are more likely to be encoun- signaling and mTOR pathways, among other functions. Mutations
tered in daily neuro-oncology practice, and thus, are covered here result in loss of expression of 1 of these 2 proteins. Two-thirds of
is less detail than the rarer syndromes above. cases represent de novo mutations.

Neurofibromatosis Type 1 von Hipple-Lindau Syndrome

Tumors Tumors
Pilocytic astrocytomas of the optic pathway,25 pilocytic or diffuse Patients with von Hipple-Lindau syndrome develop hemangio-
astrocytomas of the brainstem, cerebellum, or diencephalon,26 blastomas of the pial surface of the cerebellum and spinal cord
plexiform neurofibromas and malignant peripheral nerve sheath and of the retina.31 The lesions are usually multiple and may
tumors are some of the nervous system tumors seen in neurofi- have a clinically significant cystic component in addition to a
bromatosis type 1.27 Patients with optic pathway gliomas are at solid tumor nodule. Renal cell carcinoma is a common systemic
increased risk of additional brain tumors and radiation therapy in- cancer in these patients. Other systemic features are detailed in
creases this risk an additional 3-fold.28 Tumors tend to behave in Table 3.
a more benign manner than sporadic counterparts. Radiation
should be used with great caution due to the high rate of second Molecular Genetics
tumors. Systemic features are detailed in Table 3.
VHL is highly conserved across species and encodes the pVHL pro-
tein. Of the many functions that have been ascribed to pVHL, loss
Molecular Genetics of regulation of the hypoxia-inducible factor a pathway, leading
NF1 is a large gene that encodes neurofibromin, an activator of Ras to the formation of highly vascularized tumors, has gained the
GTPase among many other functions. Neurofibromatosis type 1 is most attention.
the most common de novo mutation to affect the nervous system,
with an incidence of 1 in 3000 births and a 50% rate of de novo
mutation.27 A very large number of mutation types are seen. Familial Glioma
Tumors
Neurofibromatosis Type 2 Approximately 5% of patients with glioma have a family member
with a glioma,1 usually affecting 1 first-degree or second-degree
Tumors
relative.32 Glioblastoma is often present in at least 1 family mem-
The typical lesions of neurofibromatosis type 2 are bilateral ves- ber but other gliomas are also seen. Compared with sporadic tu-
tibular schwannomas.29 Meningiomas, ependymomas, and mors, there are no differences with respect to age at diagnosis,
schwannomas of other cranial or peripheral nerves are also sex, or tumor characteristics. The risk of a brain tumor in addition-
seen. Bilateral vestibular schwannomas are present by age 30, al family members is low.32
and individuals with unilateral tumors diagnosed at less than
age 30 are likely to have neurofibromatosis type 2. Unilateral
Molecular Genetics
vestibular schwannomas in patients over age 30 are likely spora-
dic. Systemic features are detailed in Table 3. Although little is known regarding the molecular genetics of fami-
lial glioma, mutations in the POT1 member of the telomere shel-
terin complex have been associated with familial glioma, as well
Molecular Genetics as being implicated in a wide variety of other cancers, including
The NF2 gene encodes the merlin protein that functions in growth familial melanoma. This may explain why some studies have
factor receptor signaling and cell adhesion.29 The mutation is 10 identified a higher incidence of melanoma in first-degree relatives
times less common than neurofibromatosis type 1 and the de of glioma patients than expected by general population statistics.

10 of 12 Neuro-Oncology Practice
 Dunbar et al.: Genetic counseling and tumor predisposition

Familial oligodendrogliomas have been associated with germline 2. Hampel H, Bennett RL, Buchanan A, et al. A practice guideline from
mutations in shelterin-complex genes.33 the American College of Medical Genetics and Genomics and the
National Society of Genetic Counselors: referral indications for
cancer predisposition assessment. Genet Med. 2015;17(1):70– 87.
Other Syndromes
3. Lu KH, Wood ME, Daniels M, et al. American Society of Clinical
Sturge-Weber syndrome, also known as encephalotrigeminal Oncology Expert Statement: collection and use of a cancer family
angiomatosis, is a rare inherited disorder of blood vessels in history for oncology providers. J Clin Oncol. 2014;32(8):833– 840.
which choroid plexus papillomas may occur in addition to the typ- 4. Bonadies DC, Brierley KL, Barnett RE, et al. Adverse events in cancer
ical port-wine stain birthmark on the face within the trigeminal genetic testing: the third case series. Cancer J. 2014;20(4):246– 253.
nerve distribution. Sturge-Weber results from a postzygotic muta- 5. National Comprehensive Cancer Network. Genetic/Familial High-Risk
tion of the GNAQ gene.

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distinct clinically and genetically from neurofibromatosis type 6. American Society of Clinical Oncology. American Society of Clinical
2. In addition, familial clustering of schwannomas and other Oncology policy statement update: genetic testing for cancer
CNS tumors have been reported. In some cases this clustering susceptibility. J Clin Oncol. 2003;21(12):2397– 2406.
is due to more newly described genes not discussed here or 7. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular
due to relationships between genetic and environmental factors. diagnostic testing conundrum for Mendelian disorders in the era of
Thus, genetic risk assessment may still be appropriate even if a next-generation sequencing: single-gene, gene panel, or exome/
well-described syndrome is not suspected. genome sequencing. Genet Med. 2015;17(6):444–451.
8. Walsh T, Casadei S, Lee MK, et al. Mutations in 12 genes for inherited
Diagnostic and Therapeutic Implications ovarian, fallopian tube, and peritoneal carcinoma identified by
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tumor predisposition syndrome would suggest that these patients
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should avoid physical and chemical agents that can produce addi-
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be reasonable to avoid tests that employ x-rays (eg, CT surveillance
10. Bertherat J, Horvath A, Groussin L, et al. Mutations in regulatory subunit
of the body for systemic cancers) when possible. Ultrasound and
type 1A of cyclic adenosine 5′ -monophosphate-dependent protein
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From a therapeutic standpoint, radiation therapy and mutagen- different genotypes. J Clin Endocrinol Metab. 2009;94(6):2085–2091.
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the syndrome, especially for indolent or low-grade tumors (eg, Genetic heterogeneity and spectrum of mutations of the PRKAR1A
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diation treatment for patients with neurofibromatosis type 1. Impor- Chromosomes Cancer. 2015;54:463–471.
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