Chapter 58: Genetics of Common Inherited Cancer Syndromes

Kathleen A. Calzone; Sheila Prindiville

INTRODUCTION

Table 55–1.Indications for Genetic Testing for Cancer Susceptibility American Society of Clinical Oncology (ASCO)^1,2

Table 55–1. Indications for Genetic Testing for Cancer Susceptibility American Society of Clinical Oncology (ASCO)^1,2

Personal and/or family history suggestive of a known cancer susceptibility syndrome
The genetic test can be adequately interpreted
Genetic test results will aid in diagnosis and/or influence medical or surgical management

Testing should be performed only in the context of both pre- and posttest genetic counseling including risks, benefits and limitations of testing, early detection, and risk reduction options^1,3

ASCO also recommends that the evidence of clinical utility of any genetic test (including multiplex tests and low or moderate disease genes or SNP tests) be considered when either ordering or making medical recommendations based on a test result

Table 55–2.Selected Hereditary Cancer Syndromes⁴

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Table 55–2. Selected Hereditary Cancer Syndromes⁴

Syndrome

Gene

Mode of Inheritance

Clinical Manifestations

Basal cell nevus syndrome (Gorlin syndrome)

PTCH

Autosomal dominant

Basal cell carcinoma, medulloblastoma, ovarian fibrosarcoma, odontogenic keratocyst, palmar/plantar pits, ectopic calcification

Breast/ovarian cancer syndrome

BRCA1

Autosomal dominant

Breast, ovary, fallopian tube, prostate, pancreas, and possibly gastric, as well as other sites

BRCA2

Autosomal dominant

Breast, ovary, fallopian tube, prostate, pancreas, melanoma, and possibly gastric, as well as other sites

Cowden syndrome

PTEN

Autosomal dominant

Multiple mucocutaneous lesions, vitiligo, angiomas, benign proliferative disease of multiple organ systems, macrocephaly, breast cancer, thyroid (nonmedullary) cancer, endometrial cancer, and renal cancer, as well as other possible sites

Familial adenomatous polyposis (FAP)

APC

Autosomal dominant

Multiple colon and/or rectal adenomatous polyps (>100 polyps = FAP; < 100 polyps = attenuated FAP), polyps in the upper gastrointestinal tract, osteomas, epidermoid cysts, desmoid tumors, congenital hypertrophy of retinal pigment, dental abnormalities and cancers of the thyroid, small bowel, hepatoblastoma, and brain tumors

Familial juvenile polyposis

BRIP1A

SMAD4

Autosomal dominant

Hamartomatous polyps of the stomach, small intestine, colon and rectum. Colon cancer, as well as cancers of the stomach, duodenum, and pancreas

Fanconi anemia

FANCA

FANCB/FAAP95

FANCC

FANCD1?BRCA2

FANCD2

FANCE

FANCF

FANCG/XRCC

FANCI/KIAA1784

FANCJ/BACH1/BRIP1

FANCL/PHF9/FAAP43/POG

FANCM/FAAP250/Hef

FANCCN/PALB2

Autosomal recessive

Leukemia, hepatocellular carcinomas, squamous cell carcinomas—head/neck, esophagus, cervix, vulva, anus, hepatic adenoma, myelodysplastic syndrome, aplastic anemia

Li-Fraumeni syndrome

TP53

Autosomal dominant

Breast cancer, sarcoma, brain tumors, leukemia, adrenocortical carcinoma, as well as other possible cancers

Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer)

MLH1

MSH2

MSH6

MSH3

PMS1

PMS2

Autosomal dominant

Cancers of the colon, rectum, stomach, small intestine, biliary tract, brain, endometrium, and ovary, and transitional cell carcinoma of the ureters and renal pelvis

Melanoma

CDKN2A

CDK4

Autosomal dominant

Melanoma, astrocytoma, pancreatic cancer, ocular melanoma, as well as possibly breast cancer

Multiple endocrine neoplasm type I

MEN1

Autosomal dominant

Pancreatic and neuroendocrine tumors, gastrinomas, insulinomas, parathyroid disease, carcinoids, as well as adrenal cortical tumors, malignant schwannomas, ovarian tumors, pancreatic islet cell cancers, and gastrointestinal stromal tumors

Multiple endocrine neoplasm type II

RET

Autosomal dominant

Medullary thyroid cancer, pheochromocytoma, papillary thyroid cancer, ganglioneuromas

MYH-associated polyposis (MAP)

MYH

Autosomal recessive

Cancers of the colon and duodenum, colon, duodenal and gastric fundic gland polyps, osteomas, sebaceous gland adenomas, and pilomatricomas

Neurofibromatosis type 1

NF1

Autosomal dominant

Malignant peripheral neural sheath tumors, neurofibromas, benign pheochromocytomas, meningiomas, hamartomatous intestinal polyps, gastrointestinal stromal tumors, optic gliomas, café-au-lait macules, axillary or inguinal freckles, iris hamartomas, sphenoid wing dysplasia or congenital bowing/thinning of long bones, as well as other malignancies

Neurofibromatosis type 2

NF2

Autosomal dominant

Neurofibromas, gliomas, vestibular schwannoma, schwannomas of other cranial and peripheral nerves, meningioma, ependymomas, astrocytomas

Prostate cancer

BRCA1

BRCA2

HOXB13

RNASEL

ELAC2/HPC2

MSR1

EMSY

AMACR

KLM6

NBS1

CHEK2

MMR genes (MLH1, MSH2, MSH6, PMS2)

Several other loci under study

Varied: Autosomal dominant, autosomal recessive, X-Linked

Prostate cancer, other cancers not fully defined

Retinoblastoma

RB1

Autosomal dominant

Retinoblastoma, soft tissue and osteosarcoma, melanoma, brain tumors and nasal cavity cancers, lung cancer, bladder cancer, retinomas, lipomas

von Hippel-Lindau

VHL

Autosomal dominant

Renal cell cancer, hemangioblastoma of brain, spinal cord, and retina, renal cysts, pheochromocytomas, endolymphatic sac tumors, pancreatic islet cell tumors

Wilms tumor

WT1

Autosomal dominant

Wilms tumor, nephrogenic rests

Xeroderma pigmentosum

XPA

ERCC3

XPC

ERCC2

DDB2

ERCC4

ERCC5

POLH

Autosomal recessive

Basal and squamous cell skin cancer, melanoma, sarcoma, brain, lung, breast, uterus, kidney, and testicle cancers, leukemia, conjunctival papillomas, actinic keratosis, lid epithiomas, keratoacanthomas, angiomas, fibromas

Table 55–3.Selected Criteria for Referring a Patient to a Genetics Professional^4,5,6,✫

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Table 55–3. Selected Criteria for Referring a Patient to a Genetics Professional^4,5,6,✫

1. General indications:

Family member with documented deleterious mutation in a cancer susceptibility gene
Cancer in two or more close relatives (on same side of family)
Early age at cancer diagnosis
Multiple primary tumors
Bilateral cancer in paired organs
Multiple rare cancers in biologically related relatives
Constellation of tumors consistent with known hereditary syndrome (eg, medullary thyroid cancer and pheochromocytoma)
Rare histology

2. Breast and/or ovarian genetic syndrome assessment if patient has 1 or more of the following:

Member of a family with a known mutation in a breast cancer susceptibility gene
Age ≤45 years at diagnosis of breast cancer (including ductal carcinoma in situ [DCIS])
Age ≤50 years at diagnosis of breast cancer (including DCIS) and/or ≥1 first-, second-, or third-degree relative with epithelial ovarian cancer at any age
Two primary breast cancers with first breast cancer diagnosed at age ≤50 years
Triple-negative (ER, PR, HER2) breast cancer diagnosed at age ≤60 years
Breast cancer at any age with ≥2 first-, second-, or third-degree relatives with breast and/or epithelial ovarian cancer at any age
Breast cancer at any age with ≥2 first-, second-, or third-degree relatives with pancreatic cancer or aggressive prostate cancer (Gleason score > or = 7) at any age
Breast cancer at any age with first-, second-, or third-degree relatives with male breast cancer
Breast cancer at any age in populations at risk, for example, Ashkenazi Jewish descent
Epithelial ovarian cancer at any age
Male breast cancer at any age
Pancreatic cancer or aggressive prostate cancer (Gleason score > or = 7) at any age with ≥2 first-, second-, or third-degree relatives with breast cancer and/or ovarian and/or pancreatic cancer or aggressive prostate cancer (Gleason score > or = 7)
No history of cancer but family history consistent with any of the above criteria

3. Li-Fraumeni syndrome criteria:

Member of a kindred with a known positive TP53 mutation
Individual diagnosed with a sarcoma younger than 45 years of age and with a first-degree relative diagnosed at younger than 45 years of age with any cancer and an additional first- or second-degree relative in the same lineage with any cancer diagnosed at younger than age 45 years of age or a sarcoma at any age

4. Li-Fraumeni–like syndrome criteria:

Individual with
1. Any childhood tumor
2. Any sarcoma, brain tumor or adrenocortical carcinoma diagnosed at younger than age 45 years and
3. A first- or second-degree relative with a typical Li-Fraumeni syndrome at any age and another first- or second-degree relative with any cancer diagnosed at younger than the age of 60 years

5. Colorectal cancer (FAP/Lynch) syndrome criteria:

Family with known hereditary syndrome associated with cancer with or without mutation (eg, polyposis)
Early age onset colorectal cancer (younger than age 50 years)
Presence of synchronous or metachronous colon cancer diagnosed at any age
Colon cancer at any age with ≥1 first-, second-, or third-degree relatives with a Lynch syndrome-associated cancer with 1 cancer diagnosed at younger than age 50 years
Colon or endometrial cancer with MSI-H histology
Colon cancer at any age with ≥2 first-, second-, or third-degree relatives with a Lynch syndrome–associated cancer at any age
Endometrial cancer at <50 years of age
Clustering of same or related cancer in close relative
1. Colorectal
2. Endometrial
3. Ovarian
4. Duodenal/small bowel
5. Stomach
6. Ureteral/renal pelvis
7. Sebaceous adenomas or sebaceous carcinoma OR
Multiple colorectal carcinomas or >10 adenomas in same individual OR
History of a desmoid tumor

^✫Testing is most informative when testing an affected family member first. Testing unaffected individuals can be considered when no affected family member is available but this limits test interpretation

Table 55–4.Management Guidelines for Selected Inherited Cancer Syndromes

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Table 55–4. Management Guidelines for Selected Inherited Cancer Syndromes

Cancer Risk Management Options for Selected Cancers Associated with Hereditary Breast/Ovarian Cancer Syndrome⁵

Cancer

Test or Procedure

Frequency

Considerations

FEMALE

Breast

Mammography

Every 12 months starting at age 25 years or individualized based on the earliest breast cancer case in family, whichever is earlier

Consider offering participation in ongoing high-risk screening studies using novel imaging modalities

Breast MRI

Every 12 months starting at age 25 years or individualized based on the earliest breast cancer case in family, whichever is earlier

Risk-reducing mastectomy

Consider once childbearing/breast-feeding is complete

Clinical breast exam

Every 6–12 months starting at age 25 years

Breast awareness

Training and education starting at age 18 years

Chemoprevention

Consider on a case-by-case basis

Cancer Screening, Chapter 54 for a summary of breast chemoprevention from the table: Modified ACS Guidelines for Screening and Treating Women at Increased Risk for Breast Cancer

Ovarian

Transvaginal ultrasound with color flow Doppler

Every 6 months starting at age 30 years or 5–10 years prior to the earliest ovarian cancer case in the family

Optimal to perform on days 1–10 of menstrual cycle in premenopausal women

CA-125

Every 6 months starting at age 30 years or 5–10 years prior to the earliest ovarian cancer case in the family

Optimal to perform after day 5 of menstrual cycle in premenopausal women

Risk-reducing bilateral salpingo oophorectomy

Recommended when childbearing complete, ideally between ages 35 and 40 years or individualized based on earliest ovarian cancer case in the family

Chemoprevention: oral contraceptive

Consider on a case-by-case basis

Evidence is unclear about whether this is associated with a small increased breast cancer risk

MALE

Prostate

Digital rectal exam

Consider every year starting at age 40 years

PSA

Consider every year starting at age 40 years

Breast

Mammography

Consider baseline mammogram at age 40 years; annual mammogram if baseline exam shows gynecomastia or parenchymal glandular breast density

Clinical breast exam

Consider every 6–12 months starting at age 35 years

Breast awareness

Training and education starting at age 35 years

American Cancer Society Guidelines should be followed for cancer screening other than that outlined above

Refer to Chapter 54 for more information

Cancer Risk Management Options for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer [HNPCC])⁶

Cancer

Test or Procedure

Frequency

Considerations

Colon

Colonoscopy

Every 1–2 years starting at age 20–25 years or 2–5 years prior to the earliest age of diagnosis in the family if earlier than age 25 years

Ovarian

Transvaginal ultrasound with color flow Doppler

No evidence to support this screening but can be considered every year

CA-125

No evidence to support this screening but can be considered every year

Risk-reducing bilateral salpingo oophorectomy

Consider when childbearing complete

Endometrial

Transvaginal ultrasound with color flow Doppler

No evidence to support this screening but can be considered every year

Endometrial aspirate

No evidence to support this screening but can be considered every year

Risk-reducing hysterectomy

Consider when childbearing complete

Stomach and small bowel

Upper endoscopy

No evidence to support this screening but EGD with extended duodenoscopy can be considered every 2–3 years starting at age 30–35 years. Consider capsule endoscopy for small bowel every 2–3 years starting at age 30–35 years

Urinary tract

Urinalysis

Every year starting at age 25–30 years

Central nervous system

Physical examination

Every year starting at age 25–30 years

Pancreas

None

Data insufficient to recommend screening modality

Breast

None

There is emerging evidence that Lynch Syndrome increases breast cancer risk. Data is insufficient to recommend screening beyond American Cancer Society Guidelines for breast cancer screening

Table 55–5.Key Elements of Informed Consent for Genetic Testing for Cancer Susceptibility^1,3,4

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Table 55–5. Key Elements of Informed Consent for Genetic Testing for Cancer Susceptibility^1,3,4

Topic

Content

Purpose of test

No prior history of cancer:

Potential clarification of personal cancer risk
Risk for other family members

History of cancer:

Establishing the basis for existing cancer
Identifying risk for other cancers
Risk for other family members

Practical aspects of test

Type of analysis being performed
Cost
Insurance coverage
Biosample required (blood, buccal swab, etc.)
Timeframe for results to be available
Plan for result disclosure

Possible test outcomes

Specificity and sensitivity of test

Known deleterious mutation in family:

Negative/informative
Positive for deleterious mutation in family

No known mutation in family:

Negative/uninformative
Variant of uncertain significance
Positive for deleterious mutation
Cancer risks associated with gene if deleterious mutation identified

Psychosocial implications

Psychological:

Relief
Anxiety
Vulnerability
Anger
Depression
Guilt
Regret over prior decisions

Social:

Family implications
Patterns of transmission
Family dissemination plan for results
Testing other family members
Insurance risks (health, life, disability and long-term care insurance) and the protections provided by the Genetic Information Non-Discrimination Act (GINA)
Employment discrimination
Military discrimination

Options for medical follow-up

Benefits, limitations, and recommendations for:

Surveillance options
Prophylactic surgery options
Chemoprevention options
Risk avoidance options
Participation in clinical research

Privacy and confidentiality

Where test report will be stored
Who has access to test report
Process and considerations in disclosing to third parties

Tissue storage and reuse

Laboratories policy on:

Additional testing of identifiable samples
Length of storage of sample

Alternatives to testing

Options for:

Decline testing
Empiric risk calculations
Delay of testing
Delay in receiving results once tested
Research participation

Table 55–6.Resources

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Table 55–6. Resources

Organization

Contact Information

Resource

American Society of Clinical Oncology

http://www.asco.org

Policy statements on genetic testing for cancer susceptibility

Center for Disease Control

http://www.cdc.gov/genomics

Genomics and Disease Prevention at CDC online information resource and listserve

Gene tests

http://www.ncbi.nlm.nih.gov/sites/GeneTests/

Genetics web-based information resource on genetic syndromes, genetic testing and laboratory and clinical directories

NCI Cancer Genetic Services Directory

http://www.cancer.gov/cancertopics/genetics/directory

List of healthcare professionals who provide cancer genetic services and who meet specified criteria

OMIM Online Mendelian Inheritance in Man

http://www.ncbi.nlm.nih.gov/omim

An online catalog of information on human genes and genetic disorders

Physician's Database Query (PDQ)

http://www.cancer.gov/cancertopics/pdq/genetics

PDQ—an NCI database that contains the latest information about genetics

REFERENCES

ASCO. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 2003;21:2397–2406 [PubMed: 12692171]

Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2010;28(5):893–901 [PubMed: 20065170]

Riley BD, Culver JO, Skrzynia C et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 2012;21(2):151–161 [PubMed: 22134580]

Lindor NM, McMaster ML, Lindor CJ, Greene MH. Concise handbook of familial cancer susceptibility syndromes—2nd edition. Journal of the National Cancer Institute Monographs, 2008;38:1–93

NCCN. NCCN Practice Guidelines for Prevention, Detection and Risk Reduction. Genetic/Familial High-Risk Assessment: Breast and Ovarian (2.2013). [Cited June 5, 2013] Available from: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf (2013)

NCCN. NCCN Practice Guidelines for Prevention, Detection and Risk Reduction. Colorectal Cancer Screening (1.2013). [Cited June 5, 2013] Available from: http://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf (2013)

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Chapter 58: Genetics of Common Inherited Cancer Syndromes

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INTRODUCTION

REFERENCES

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