The Bethesda Handbook of Clinical Oncology

Holly Jane Pederson and Brandie Heald

INTRODUCTION

Clinical genetics is the specialty that involves the diagnosis and management of hereditary disorders. As an oncology healthcare provider, recognition of these syndromes is critical in order to provide proper care related to cancer therapy decisions, to identify other risks for that patient, and to counsel family members about risks and options. Hereditary cancers are important to detect because the age of onset is early, multiple primary cancers can develop, and cancer predisposition may be inherited. Hereditary syndromes account for only a minority of cases of cancer, but those who are affected have extremely high risks. Patients at increased risk may benefit from enhanced surveillance, chemopreventive strategies, or risk-reducing surgeries.

If a hereditary cancer syndrome is suspected (Table 44.1), a focused exam specific to the syndrome (i.e., dermatologic and head circumference for PTEN-hamartoma tumor syndrome), and genetic counseling with an expanded pedigree detailing the types of cancer, bilaterality, age at diagnosis, ethnicity, and medical record documentation as needed (i.e., pathology reports of primary cancers or carcinogen exposure) should be done. Prior to genetic testing, patients must give informed consent with an understanding of the benefits, risks, and limitations of testing as well as the goals for cancer family risk assessment in alignment with the American Society of Clinical Oncology policy statement on genetic testing. Options exist for family planning including pre-implantation genetic testing and prenatal diagnosis. Patients should be made aware of the Genetic Information Nondiscrimination Act (GINA) of 2008, which prohibits employment and health insurance discrimination based on genetic information.

The tenets of genetic counseling are relevant to hereditary cancer syndromes. A detailed, four generation family tree is elicited, and this information, together with the personal history of the patient, allows the counselor to determine if the presentation is most suggestive of sporadic, familial, or hereditary cancer. This comprehensive risk assessment ensures that the correct genetic testing is offered to the most appropriate patients, with personalized interpretation of results and provision of future management recommendations. Guideline driven management recommendations are available for many syndromes.

TABLE 44.1Hereditary Cancer Syndromes

Syndrome	Gene	Associated Cancers/Tumors
Birt-Hogg-Dube	*FLCN*	RCC
Familial adenomatous polyposis	APC	Colon, gastric, small bowel, thyroid, brain
Familial medullary thyroid cancer	RET	Medullary thyroid
Familial papillary renal cancer	MET	Type 1 papillary RCC
Fanconi anemia	Multiple genes including biallelic BRCA2 mutations; diagnosis is made by increased chromosomal breakage in lymphocytes cultured in the presence of DNA cross-linking agents	AML, MDS, solid tumor especially squamous cell carcinoma of the head and neck or vulva. Breast cancer if associated with biallelic BRCA2 mutations
Gorlin syndrome	PTCH	Basal cell, medulloblastoma
Hereditary breast and ovarian cancer syndrome	BRCA1, BRCA2	Breast, ovarian, prostate, pancreatic, melanoma, male breast cancer
Hereditary diffuse gastric cancer	CDH1	Diffuse gastric cancer, lobular breast cancer
Hereditary leiomyomatosis	FH	Type 2 papillary RCC
Hereditary melanoma	CDKN2A, CDK4	Melanoma, pancreas
Juvenile polyposis syndrome	BMPR1A, SMAD4	Juvenile/hamartomatous gastrointestinal polyposis, colorectal, gastric, hereditary hemorrhagic telangiectasia (SMAD4 only)
Li–Fraumeni syndrome	TP53	Breast, sarcoma, leukemia, brain tumors, adrenocorticoid, lung bronchoalveolar
Lynch syndrome	MLH1, MSH2, MSH6, PMS2, EPCAM	Colon, endometrial, ovarian, gastric, small bowel, biliary, pancreatic, upper urinary tract, skin, brain
Multiple endocrine neoplasia type 1	MEN1	Parathyroid, pituitary, pancreatic, or extrapancreatic
Multiple endocrine neoplasia type 2A	RET	Medullary thyroid, pheochromocytoma, parathyroid
Multiple endocrina neoplasia type 2B	RET	Medullary thyroid, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas
MUTYH-associated polyposis	MUTYH	Similar to FAP
Peutz–Jeghers syndrome	STK11	Colon/rectum, breast, stomach, small bowel, pancreas, lung, cervix, ovaries, testicles
PTEN-hamartoma tumor syndrome	PTEN	Breast, endometrial, thyroid, kidney, melanoma, and colorectal
Von Hippel–Lindau disease	VHL	Clear cell RCC, pheochromocytomas, neuroendocrine

In this chapter we will review the most commonly seen and tested hereditary cancer syndromes in adults.

HEREDITARY BREAST CANCER SYNDROMES

Hereditary Breast and Ovarian Cancer Syndrome

Hereditary breast cancer accounts for 5% to 10% of all breast cancers. The most common hereditary breast cancer syndrome involves pathogenic variants in the BRCA1/2 genes, tumor suppressor genes that play a role in double-stranded DNA repair. These mutations account for 65% of hereditary breast cancer and have an autosomal dominant pattern of inheritance. The incidence is 1 in 400 for the general population and 1 in 40 in the Ashkenazi Jewish population.

Pathogenic variants in these genes are associated with significantly elevated risks of both breast cancer (up to 87%) and ovarian cancer (up to 54%) and earlier age of onset of both cancers. The BRCA1 gene can frequently be associated with triple-negative breast cancer histology and both genes are associated with serous ovarian cancer. Other cancers such as pancreatic cancer, prostate cancer, male breast cancer, and melanoma can also be seen, particularly in patients with BRCA2 gene mutations. BRCA1/2 testing is recommended per guidelines set forth by the National Comprehensive Cancer Network (NCCN) in individuals:

from a family with a known pathogenic variant in BRCA1 or BRCA2

with a personal history of breast cancer and one of the following:

•diagnosed at 45 years of age or younger

•diagnosed at 50 years of age or younger with:

•an additional breast cancer primary

•a close blood relative with breast cancer at any age

•a relative with pancreatic cancer

•a relative with prostate cancer (Gleason score greater than or equal to 7)

•an unknown or limited family history

•diagnosed at 60 years of age or younger with triple negative breast cancer

•diagnosed at any age with:

•one or more close blood relatives with breast cancer diagnosed at the age of 50 or younger

•two or more blood relatives with breast cancer diagnosed at any age

•one or more close blood relatives with ovarian cancer

•two or more blood relatives with pancreatic cancer and/or prostate cancer (Gleason score greater than or equal to 7) at any age

•a close male blood relative with breast cancer

•Ashkenazi Jewish ancestry

•with a personal history of ovarian cancer

•with a personal history of male breast cancer

•with a personal history of metastatic prostate cancer

•with a personal history of a somatic BRCA mutation

As with all hereditary syndromes, testing of unaffected individuals should only be considered when an affected family member is unavailable or unwilling to test and family history reveals a first- or second-degree relative meeting the above criteria. In this circumstance, the significant limitations of interpreting results should be discussed since negative test results in an unaffected individual are uninformative.

If a BRCA pathogenic variant is found, general options for risk management include enhanced surveillance, chemoprevention, and risk reducing surgery. Breast self-awareness is recommended starting at the age of 18. Women should be familiar with their breasts and report changes to their healthcare provider. Periodic, consistent breast self-exam (BSE) may facilitate breast self-awareness. Clinical breast examination is recommended every 6 to 12 months starting at age 25. Annual MRI screening is recommended beginning at the age of 25 until the age of 75 and annual screening mammograms should begin at 30. MRI has been shown to be more sensitive for cancer detection in this population. Risk-reducing mastectomy can reduce the risk of breast cancer by 90%. Counseling should include a discussion regarding the degree of protection, reconstructive options, and surgical risks. Data with tamoxifen for prevention in this population is limited but suggestive of reduction of ER+ disease, particularly in patients with a BRCA2 mutation. Given the elevated risk for ovarian cancer and the lack of effective screening, risk-reducing salphingo-oopherectomy (RRSO) is recommended between the ages of 35 and 40, or upon completion of childbearing, and may reduce breast cancer risk, particularly in BRCA2 carriers. This has been the only intervention thus far shown to reduce overall mortality. Because ovarian cancers occur in patients with BRCA2 mutations an average of 8 to 10 years later than in patients with BRCA1 mutations, it is reasonable to delay RRSO until age 40 to 45 in patients with BRCA2 mutations who have already maximized their breast cancer risk reduction (have undergone RRM). Counseling includes a discussion of reproductive desires, extent of cancer risk, degree of protection for breast and ovarian cancer, management of menopausal symptoms, possible short-term hormone replacement therapy to a recommended maximum age of natural menopause, and related medical issues. Salpingectomy alone is not the standard of care for risk reduction although clinical trials are ongoing as the majority of serous ovarian cancers are felt to originate in the fallopian tubes. The concern for risk-reducing salpingectomy alone is that women may still be at risk for developing ovarian cancer, and that risk is of yet undefined. In addition, in premenopausal women, oophorectomy reduces the risk of developing breast cancer in BRCA2 carriers by up to 50% depending upon age of procedure. For those patients who have not elected RRSO, while there may be circumstances where clinicians find screening helpful, data do not support routine ovarian screening. Transvaginal ultrasound for ovarian cancer screening has not been shown to be sufficiently sensitive or specific to support a positive recommendation, but may be considered at the clinician’s discretion starting at the age of 30 to 35. Serum CA125 is an additional ovarian screening test with caveats similar to transvaginal ultrasound.

For men, the risk of breast cancer is 7% and more common in BRCA2 carriers. Breast self-examination should start at the age of 35. Clinical examination should begin annually at 35, and prostate cancer screening is recommended starting at the age of 45. No specific screening guidelines exist for pancreatic cancer and melanoma, but screening may be individualized based on cancers observed in the family. There is only limited data to support breast imaging in men.

PTEN-Hamartoma Tumor Syndrome

PTEN-hamartoma tumor syndrome (PHTS) is a genetic diagnosis that encompasses the conditions Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. It is an autosomal dominant syndrome with an incidence of 1 in 200,000. It is caused by a loss of function in the tumor suppressor PTEN gene and is associated with multiple hamartomas in a variety of tissues, characteristic dermatologic manifestations, and an increased risk of breast, endometrial, thyroid, kidney, melanoma, and colorectal cancers. The lifetime risk of breast cancer may be as high as 85% in patients with documented pathogenic variants in the PTEN gene. Thyroid cancer, typically follicular and rarely papillary, develops in two-third of carriers and can occur in childhood. Renal cell carcinoma can be seen in 13% to 34% of carriers. The prevalence of colon polyps is 66% to 93%. While hamartomatous polyps have predominantly been reported, patients with PHTS often develop a mix of ganglioneuromas, hamartomatous, adenomatous, serrated, and inflammatory polyps. This lifetime risk of developing colorectal cancer is as high as 16%. Neurologic manifestations include dysplastic gangliocytoma of the cerebellar cortex, macrocephaly, intellectual disability, and autism. Women commonly have benign abnormalities such as significant fibrocystic breast changes, breast hamartomas, uterine fibroids, and ovarian cysts. Men often have lipomatosis of the testes. Both men and women frequently have benign thyroid lesions, such as adenomas and multinodular goiter. Benign glycogenic acanthosis and lipomas can also be seen.

Genetic testing criteria are divided into major and minor criteria. The major criteria include breast cancer, follicular thyroid cancer, multiple gastrointestinal hamartomas or ganglioneuromas, macrocephaly, endometrial cancer, penile freckling, and characteristic mucocutaneous lesions. The minor criteria include Autism spectrum disorder, colon cancer, ≥3 esophageal glycogenic acanthuses, lipomas, intellectual disability, papillary or follicular variant of papillary thyroid cancer, structural thyroid lesions, renal cell carcinoma, single gastrointestinal hamartoma or ganglioneuroma, testicular lipomatosis, and vascular anomalies. PTEN testing should be offered to individuals with the following:

two or more major criteria (one must be macrocephaly)

three major criteria, without macrocephaly

one major and three or more minor criteria

four or more minor criteria

adult Lhermitte-Duclos disease

autism spectrum disorder and macrocephaly

two or more biopsy-proven trichilemmomas

For those with a family member with a clinical diagnosis of Cowden syndrome or PHTS, genetic testing should be offered when any major criterion or two minor criteria are present. Clinical diagnostic Cowden syndrome criteria, which vary slightly from the testing criteria, have been established by the NCCN and International Consortium Cowden Consortium. The estimated lifetime risk of developing breast cancer in a patient with Clinical Cowden Syndrome is felt to be 25% to 50%. PTEN testing includes sequencing of the entire coding region and deletion/duplication analysis. Pathogenic variants have also been reported in the PTEN promoter region. Other candidate genes for Cowden syndrome are actively being investigated. De novo mutations are not uncommon.

The NCCN management guidelines for women with PHTS include breast self-examination training and education starting at age 18, clinical breast examination every 6 to 12 months starting at age 25, and annual mammography and breast MRI starting at age 30 to 35 or individualized based on the earliest age of onset in family. For endometrial cancer screening, consideration can be given to annual random endometrial biopsies and/or transvaginal ultrasound beginning at age 30 to 35. Risk-reducing mastectomies and hysterectomy can be considered. Men and women should have an annual physical examination starting at age 18 or 5 years prior to the youngest age of diagnosis of cancer in their family with emphasis on thyroid examination. Baseline thyroid ultrasound should be done at the time of diagnosis and annually thereafter. Screening colonoscopies should begin at age 35 with follow-up every 5 years. Consider renal ultrasound every 1 to 2 years beginning at age 40 years.

Li–Fraumeni Syndrome

Li–Fraumeni syndrome is a hereditary syndrome associated with a wide range of cancers that appear at an unusually young age. LFS has an autosomal dominant pattern of inheritance and is associated with pathogenic variants in the TP53 tumor suppressor gene, which plays a major role in DNA repair. The lifetime risk of cancer is nearly 100%, with 90% of individuals diagnosed with cancer by age 60. The classic tumors seen in this syndrome are sarcoma, breast cancer, leukemia, brain tumors, and adrenal gland cancers.

Classic Li–Fraumeni criteria include a proband with sarcoma before the age of 45, a first-degree relative with cancer before the age of 45, and a first- or second-degree relative with cancer before the age of 45 or sarcoma at any age. Chompret criteria include one of the following:

a proband who has a tumor belonging to the LFS spectrum (sarcoma, premenopausal breast cancer, brain tumor, adrenocorticoid tumor, leukemia, or lung bronchoalveolar cancer) before age 46 and at least one first- or second-degree relative with a tumor in the LFS spectrum before age 56 or with multiple tumors.

a proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS spectrum and the first of which occurred before age 46.

a proband who is diagnosed with adrenocortical tumor or choroid plexus tumor regardless of age irrespective of family history.

Testing of individuals who meet either of these criteria or women with breast cancer before age 35 who have tested negative for the BRCA1/2 variants is recommended. De novo mutations occur in 7% to 20% of patients.

The management guidelines for women with LFS include breast self-examination training and education starting at age 18 and clinical breast examination every 6 to 12 months starting at age 20 to 25. In the 20s, annual breast MRI is recommended or mammogram, if MRI is not available. Beginning at age 30, annual breast MRI alternating with low dose digital mammography is recommended. Risk-reducing mastectomies should be offered as an option. All carriers should have an annual physical examination, including dermatologic and neurologic examinations. Colonoscopy screening should be considered starting at age 25 with follow-up every 2 to 5 years. Other options for screening should be discussed with the patient such as whole-body MRI, and brain MRI. Targeted surveillance should be based on family history. Therapeutic radiation should be avoided if possible.

HEREDITARY GASTROINTESTINAL SYNDROMES

Lynch Syndrome

Lynch syndrome is an autosomal dominant disorder characterized by germline pathogenic variants in the DNA mismatch repair (MMR) genes or EPCAM. Lynch syndrome accounts for 2% to 3% of all colorectal cancers and is associated with a 15% to 74% lifetime risk of developing colorectal cancer. Lifetime risk of colorectal cancer can be further stratified by gender and MMR gene, with male MLH1 carriers being at the highest risk. Compared to those with sporadic colorectal cancer, Lynch syndrome–associated colorectal cancers are usually younger at time of diagnosis (44–61 vs. 69 years old in the general population) and have more poorly differentiated, mucinous tumors found in the right colon. Despite these more aggressive histologic features, affected patients have better 5-year survival rates compared to those with common sporadic colorectal cancer. For those diagnosed with one colorectal cancer, treated with limited resection, the risk of developing another colorectal cancer 10 years after an initial diagnosis is 16% to 19%. At 20 years, this risk is 41% to 47%, and by 30 years, this risk reaches as high as 69%.

Endometrial carcinoma is the most common extra-colonic tumor in Lynch syndrome, accounting for about 2% of all endometrial cancers, with a lifetime risk ranging from 14% to 71% in female carriers. Similar to colorectal cancer in Lynch syndrome, women are typically younger in age at diagnosis (50s vs. 65 years old in the general population). Other organs at increased risk of cancer include the ovaries (4% to 20% lifetime risk), stomach (0.2% to 13%), small bowel (0.4% to 12%), pancreas/hepatobiliary tract (0.02% to 4%), upper urinary tract (0.2% to 25%), skin (1% to 9%), and brain (1% to 4%). In many families, breast and/or prostate cancers are seen, though risk has not been clearly defined.

Defects in the MMR system, which identifies base-pair mismatches and repairs them, is the hallmark characteristic of Lynch syndrome. The MMR genes affected in Lynch syndrome include MLH1, MSH2, MSH6, and PMS2. A germline deletion in EPCAM, which inactivates MSH2, has also been associated with Lynch syndrome. MMR and EPCAM mutations are inherited in an autosomal dominant manner. For an individual with Lynch syndrome, if the second allele is inactivated through one of several mechanisms (acquired somatic mutation, loss of heterozygosity, promoter hypermethylation), a defective MMR system ensues, resulting in a failure to repair DNA mismatches and an increased rate of mutations (genomic instability). DNA mismatches tend to occur in areas of repeated nucleotide sequences called microsatellites. An accumulation of mutations in these regions leads to expansion or contraction of the microsatellites, termed microsatellite instability (MSI). Approximately 90% to 95% of Lynch syndrome–associated colorectal cancers will display high levels of microsatellite instability (MSI-H).

Biallelic inheritance of mutations in one of the MMR genes causes constitutional mismatch repair-deficiency syndrome (CMMRD) and is associated with the development of Lynch syndrome–associated cancers, as well as childhood cancers, hematologic malignancies, polyposis, brain tumors, and neurofibromatosis features such as café-au-lait spots.

Patients with colorectal or endometrial cancer suspected of having Lynch syndrome can be screened through the detection of MSI by polymerase chain reaction (PCR) or the absence of the MMR protein product by immunohistochemistry (IHC). PCR detects MSI by identifying expansion or contraction of the microsatellite regions. If 30% or more of the microsatellites show instability, then the tumor is considered to have high levels of microsatellite instability (i.e., MSI-H), suggesting a defect in a DNA MMR gene. IHC uses antibodies to detect MMR proteins. Unlike MSI testing, IHC has the advantage of identifying the missing protein product, and by proxy, implicating the potentially mutated gene. An estimated 88% of colorectal cancers caused by Lynch syndrome will have abnormal IHC results. Confirmation of Lynch syndrome requires germline testing of the MMR gene(s).

Microsatellite instability is sensitive but not specific for Lynch syndrome. MSI-H can be found in up to 15% of sporadic colorectal cancers, most commonly due to the loss of MLH1 via hypermethylation of the MLH1 promoter region. Approximately 50% of colorectal cancers with MLH1 promoter hypermethylation will have a somatic BRAF V600E mutation, which is rarely seen in Lynch syndrome tumors. Endometrial cancers with MLH1 promoter hypermethylation do not have somatic BRAF mutations, so BRAF testing is not a useful tool for testing endometrial cancers. In patients who have MSI-H colorectal tumors with loss of MLH1, testing for the BRAF V600E mutation (colorectal cancer only) or MLH1 promoter hypermethylation (colorectal or endometrial cancers) should be done to rule out sporadic cases. If these tests are negative, then patients should be offered germline MLH1 testing. The loss of other MMR proteins in colorectal or endometrial cancers should proceed directly to MMR gene testing and genetic counseling. An estimated 50% of individuals with abnormal MSI/IHC results will have a germline MMR mutation. Approximately 40% of patients with abnormal MSI/IHC results will have acquired somatic MMR mutations, which is not Lynch syndrome. If an MMR mutation is not detected on germline testing then consideration should be given to MMR gene testing on the tumor DNA.

Identifying patients who have Lynch syndrome remains a challenging task. The Amsterdam I criteria were originally developed to identify individuals appropriate for hereditary colorectal cancer research. The Amsterdam II Criteria were later broadened to include other cancers observed in these families. The Amsterdam Criteria are useful for identifying patients appropriate for genetic counseling and testing. Those families that meet the Amsterdam Criteria are given a clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC). An estimated 50% of families with HNPCC will actually have Lynch syndrome. The Revised Bethesda guidelines were created to help identify colorectal cancers appropriate for MSI/IHC testing.

Amsterdam II Criteria

1.Three or more relatives with HNPCC-associated cancers (colorectal, endometrial, small bowel, ureter, or renal pelvis) cancer, one of whom is a first-degree relative of the other two.

2.Two or more generations with the above cancer(s).

3.At least one individual with the above cancer(s) in the family who was diagnosed before age 50.

4.The family does not have a different inherited colorectal cancer genetic condition called “familial adenomatous polyposis.”

Revised Bethesda Guidelines:

Colorectal cancer in a patient younger than 50 years.

Colorectal cancer with MSI-H histology in a patient younger than 60 years.

Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age.

A patient with colorectal cancer who has one or more first-degree relatives with an HNPCC-associated tumor, with one of the cancers diagnosed under the age of 50.

A patient with colorectal cancer who has two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.

Given the reduced sensitivity and specificity of the Amsterdam Criteria and Bethesda Guidelines, in 2009 the Evaluation of Genomic Application in Practice and Prevention (EGAPP) endorsed universally screening all newly diagnosed colorectal cancer with MSI and/or IHC.

For patients with Lynch Syndrome, colorectal cancer surveillance with colonoscopies should begin at the age of 20 to 25 with follow up every 1 to 2 years until age 40 when annual colonoscopy should commence. Patients must be aware that dysfunctional uterine bleeding warrants evaluation. There is no clear evidence to support screening for endometrial cancer for Lynch syndrome. However, annual office endometrial sampling is an option. While there may be circumstances where clinicians find screening helpful, data do not support routine ovarian screening for Lynch syndrome. Controversy exists surrounding the screening of other extracolonic cancers. No firm recommendations have been established except for annual skin surveillance. Upper endoscopy with visualization of the duodenum can be considered every 3–5 years starting at age 30–35 years. Primary prophylactic colectomy is generally not recommended. An annual urinalysis can be considered starting at age 30 to 35. Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be considered in high-risk patients who are 35 years or older or have finished childbearing.

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by the presence of colorectal adenomatous polyposis. FAP is caused by germline pathogenic variants in the tumor suppressor adenomatous polyposis coli (APC) gene located on chromosome 5. FAP has a number of associated extracolonic carcinomas, but unlike colorectal cancer which has near complete penetrance, the penetrance for extracolonic tumors is variable.

FAP accounts for less than 1% of all colorectal cancers. Seventy-five percent of FAP cases inherit a germline APC mutation, whereas the remaining 25% of patients are de novo cases. Among patients with >1,000 adenomas, APC pathogenic variants are identified in 80%. The mutation detection rate drops to 56% (100 to 999 colorectal adenomas), 10% (20 to 99 adenomas), and 5% (10 to 19 adenomas).

Based on the colorectal adenoma burden, two classes of FAP have been described: classic/profuse FAP and attenuated FAP (AFAP). Patients with classic or profuse FAP have greater than 100 adenomatous polyps. Adenomas typically begin to develop around puberty, and, without surgical intervention the risk of colorectal cancer is 100%. The average age of colorectal cancer diagnosis is in the third decade of life. AFAP is characterized by less than 100 adenomas, which typically begin to develop in the late teenage years or early 20s. A lower, yet still significant, risk of colorectal cancer development is seen (up to 80%) with a later age of cancer diagnosis, often in the fifth decade of life.

Patients with FAP can also develop upper gastrointestinal tracts polyps. Fundic gland polyps and gastric adenomas develop in 12% to 84% of patients. The gastric cancer risk is low but increased over the general population. Duodenal adenomas develop in 50% to 90% of patients. The risk of duodenal cancer ranges from 4% to 12% is based on the Spigelman score.

Extraintestinal manifestations, both malignant and benign, are observed in individuals with FAP. Malignant extraintestinal tumors are rare and include papillary thyroid cancer, pancreatic cancer, childhood hepatoblastoma, and central nervous system (CNS) tumors. Benign findings include desmoid tumors, sebaceous or epidermoid cysts, lipomas, osteomas, fibromas, dental abnormalities, adrenal adenomas, and congenital hypertrophy of the retinal pigment epithelium (CHRPE). Turcot syndrome was previously used to refer to the association of familial colon cancer with CNS tumors. This includes medulloblastomas observed in FAP kindred. Gardner syndrome refers to families with FAP who also have osteomas and soft tissue tumors. Turcot syndrome associated with adenomatous polyposis and Gardner’s syndrome are both forms of FAP caused by APC variants.

FAP should be suspected in any patient with 10 or more colorectal adenomas, and genetic counseling and testing for germline mutation of the APC gene should be offered to these patients. Testing for MUTYH-associated polyposis (see below) should also be considered in those who test negative for a mutation in the APC gene. Unlike most other hereditary cancer syndromes, genetic counseling and predictive genetic testing should be offered to children, generally around the age of 8 to 10 years.

Per the NCCN guidelines, screening flexible sigmoidoscopy or full colonoscopy should begin around puberty for classic/profuse type FAP with annual follow-up. Those with AFAP patients should begin screening colonoscopy in the late teenage years with follow-up every 2 to 3 years. Patients found to have profuse polyposis, multiple large (>1 cm) adenomas, or adenomas with villous histology or high-grade dysplasia should be treated with colectomy followed by routine surveillance of the ileal pouch. AFAP patients with less disease burden can undergo polypectomy followed by continued annual surveillance. Upper endoscopy with visualization of the ampulla should begin around age 20 to 25. Those with no duodenal polyposis should repeat endoscopy in 4 years. Those with Spigelman stage I (minimal polyposis; 1 to 4 tubular adenomas, size 1 to 4 mm) need repeat endoscopy in 2 to 3 years, those with stage II (mild polyposis; 5 to 19 tubular adenomas, size 5 to 9 mm) follow-up every 1 to 3 years, and those with stage III (moderate polyposis; 20 more lesions, or size 1cm or greater) every 6 to 12 months. Patients with stage IV duodenal disease (dense polyposis or high-grade dysplasia) should have surveillance every 3 to 6 months and be sent for surgical evaluation to consider mucosectomy, duodenectomy, or a Whipple procedure. Annual examination of the thyroid should commence in the late teenage years; thyroid ultrasound can be considered. For families with desmoid tumors, abdominal MRI or CT could be considered 1 to 3 years post-colectomy and every 5 to 10 years thereafter. Data are presently insufficient to support any additional screening or surveillance.

MUTYH-associated Polyposis

MUTYH-associated polyposis (MAP) is an autosomal recessive hereditary cancer syndrome characterized by adenomatous polyposis and early onset colorectal cancer. MUTYH is a base excision repair protein that plays a major role correcting in G:C>T:A transversions in the DNA. Among those of a northern European background, two common pathogenic variants c.536A>G (p.Tyr179Cys) and c.1187G>A (p.Gly396Asp) have been reported to account for up to 80% of MUTYH mutations. An estimated 1% to 2% of individuals from this ethnic group carry one of these mutations. Different founder mutations have been reported in those of Dutch, Italian, British Indian, Pakistani, Spanish, Portuguese, Tunisian, Brazilian, French, Japanese, and Korean backgrounds.

The majority of patients develop ten to hundreds of colorectal adenomas; profuse polyposis is typically not observed. Some individuals will also develop serrated polyps (hyperplastic polyps, sessile serrated adenomas/polyps, and serrated adenomas). The average age of diagnosis is around age 50 years. A rare subset of patients will present with early onset colorectal cancer in the absence of polyposis. The lifetime risk of developing colorectal cancer for individuals with MAP ranges from 43% to 100%.

Patients with MAP also develop upper gastrointestinal tract neoplasms. Approximately 10% to 15% of patients will develop fundic gland polyps and/or gastric adenomas. It is unclear if MAP is associated with an increased risk of gastric cancer. Approximately 17% to 25% of patients will develop duodenal adenomas, with an estimated 4% lifetime risk of developing duodenal cancer.

Other cancers, including thyroid, skin, endometrial, ovarian, breast, and bladder, have been reported at an increased incidence in MAP patients. Additionally, patients have been reported to have benign thyroid disease, dermatologic findings, dental abnormalities, and CHRPE.

There is speculation that MUTYH carriers may have an increased risk of developing colorectal cancer. Odd ratios among carriers have been reported between 1.1 to 1.2 and 2 to 3.

The NCCN recommends beginning colonoscopy at age 25 to 30 for those with biallelic MUTYH mutations. If negative, the exam should be repeated every 2 to 3 years. If polyps are identified, colonoscopy and polypectomy should be repeated every 1 to 2 years. Colectomy should be considered when the polyp burden is >20 on a single exam, when polyps have been previously ablated, when some polyps reach >1 cm, or when advanced histology is encountered. The adenoma distribution and polyp burden should inform the extent of colectomy. Upper endoscopy with visualization of the ampulla could be considered beginning at age 30 to 35. Follow-up is based on Spigelman score, as discussed in the FAP section. For monoallelic MUTYH carriers the NCCN currently endorses beginning colonoscopy at age 40, or 10 years earlier than the age of a first degree relative with colorectal cancer, whichever is younger, with follow-up at least every 5 years.

Hereditary Diffuse Gastric Cancer

Hereditary diffuse gastric cancer is an autosomal dominant disorder caused by germline pathogenic variants in the CDH1 gene that codes for E-cadherin, a cell-adhesion protein that allows cells to interact with each other and is critical for cell development, differentiation, and architecture. Individuals who harbor these germline mutations have a greater than 70% lifetime risk of developing diffuse gastric cancer by age 80 with a median age of onset of 38. These gastric cancers form beneath an intact mucosal surface, causing gastric wall thickening rather than the formation of a discrete mass. Because they are only visible late in the disease process, early detection is extremely challenging. Therefore, screening of high-risk individuals via EGD with random biopsies should begin in the late teenage years. Prophylactic gastrectomy should be offered to all CDH1 mutation carriers between the ages of 18 and 40.

Like diffuse gastric cancer, the absence of E-cadherin expression is also the key underlying defect in lobular breast carcinoma. Female carriers therefore have a 42% lifetime risk of developing lobular breast carcinoma by age 80. Given this considerable risk for breast cancer, annual MRI screening in addition to annual screening mammography is recommended generally 10 years earlier than the first affected relative, or beginning at age 30. Risk reducing mastectomy is considered in patients with compelling family history.

Expert opinion clinical criteria for HDGC are as follows:

two cases of gastric cancer regardless of age, at least one confirmed diffuse gastric cancer

one case of diffuse gastric cancer <40 years

personal or family history of diffuse gastric cancer and lobular breast cancer, one diagnosed <50 years

In 2015 experts also suggested that CDH1 genetic testing could be considered for those with the following:

bilateral lobular breast cancer or family history of two or more cases of lobular breast cancer <50

a personal or family history of cleft lip/palate in a patient with diffuse gastric cancer

in situ signet ring cells and/or pagetoid spread of signet ring cells

CDH1 mutation detection rates were previously reported to be 25% to 50% for those who met clinical criteria. With the expansion of the above testing criteria, the mutation detection rate has decreased to 10% to 18%.

Peutz–Jeghers Syndrome

Peutz–Jeghers syndrome (PJS) is a rare, autosomal dominant disorder characterized by multiple gastrointestinal hamartomatous polyps, mucocutaneous pigmentation, and an increased risk of malignancies. Approximately 88% of patients with PJS will develop Peutz-Jeghers polyps. Peutz-Jeghers polyps are characterized by a cerebriform appearance due to smooth muscle arborization within the polyps. These polyps often begin to develop in the first decade of life and are most common in the small bowel but can be observed in the colon, rectum, and stomach. An estimated 50% of patients will present with intussception by age 20. PJS is often recognized by characteristic mucocutaneous pigmentation. The lesions are small (1 to 5 mm in size), flat, blue-gray to brown spots, and are commonly found around the mouth and nose, in the buccal mucosa, hands and feet, perianal areas, and genitals. Over time this pigmentation can fade. Malignancies are also commonly seen in PJS and affected patients carry up to an 80% to 90% lifetime risk of developing cancer. The most common malignancies occur in the colon and rectum, but an increased risk is also seen in the breast, stomach, small bowel, pancreas, lung, cervix, ovaries, and testicles.

The World Health Organization (WHO) established clinical criteria for PJS:

three or more histologically confirmed Peutz-Jeghers polyps

any number of Peutz-Jeghers polyps and a family history of PJS

characteristic mucocutaneous pigmentation and a family history of PJS

any number of Peutz-Jeghers polyps in an individual with characteristic mucocutaneous pigmentation

Germline mutations in STK11 cause PJS. STK11 mutations are found in 60% to 99% of patients who meet the WHO criteria. Annual screening breast MRI beginning at 25 in addition to annual screening mammography beginning at 30 is recommended. Individuals with PJS should receive a colonoscopy every 2 to 3 years, beginning in the late teens. Additional guidelines for screening of the stomach, small bowel, pancreas, uterus, ovaries, and testes are outlined in NCCN guidelines.

Juvenile Polyposis Syndrome

Juvenile polyposis syndrome (JPS) is caused by mutations in the genes BMPR1A and SMAD4. This syndrome is characterized by gastrointestinal hamartomatous polyps and increased malignancy risk. Juvenile describes the hamartomatous polyps observed in this syndrome. Polyps often begin to develop in the teenage years and are most common in the colon and rectum. Patients with SMAD4 pathogenic variants can also develop massive gastric polyposis, which is more rarely observed in those with BMPR1A pathogenic variants. Small bowel polyps have been reported but are rare. The lifetime risk of developing cancer ranges from 17% to 68%, with a 50% lifetime risk of developing colorectal cancer. The risk of gastric or duodenal cancer is 15% to 21%. Germline SMAD4 mutations have also been associated with hereditary hemorrhagic telangiectasia (HHT) and aortopathy. Clinical criteria have been established for JPS:

more than three to five juvenile polyps of the colon or rectum

juvenile polyps throughout the gastrointestinal tract

any number of juvenile polyps and a positive family history of JPS

Among those that meet clinical criteria, SMAD4 and BMPR1A mutations are identified in approximately 40% to 50% of patients.

Colonoscopy and upper endoscopy should begin around age 15 years with follow-up every 1 to 3 years. Colectomy and/or gastrectomy may be considered in cases where polyp burden is endoscopically unmanageable. Individuals with SMAD4 mutations should undergo screening for HHT.

Testing Considerations

There is a shifting paradigm to move from single syndrome testing to performing next generation sequencing of multiple genes (panel testing). Gene panels include highly penetrant genes with established clinical utility; these panels also contain genes for which clinical validity or significance is less certain at this time. Since 2014, NCCN guidelines have recognized the impact that multi-gene panel testing has in changing the clinical approach to testing at-risk individuals. Panel testing may be a cost effective and efficient option, especially for individuals who have personal or family histories that are suspicious for more than one hereditary cancer syndrome, or for those who previously tested negative on single syndrome testing. In patients referred for BRCA1 and BRCA2 testing, for example, use of a 25-gene panel test in one study resulted in identification of genes other than BRCA1 and BRCA2 in 4.3% of patients. In another large prospective study of a sequential series of breast cancer patients, 10.7% were found to have a germline pathogenic variants in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes, including 6.1% in BRCA1 and BRCA2, and 4.6% in other breast/ovarian predisposition genes. Whereas young age (P < 0.01), Ashkenazi Jewish ancestry (P < 0.01, triple negative breast cancer (P = 0.01) and family history of breast/ovarian cancer (P = 0.01) predicted for BRCA1 and BRCA2 mutations, no factors predicted for mutations in other breast cancer predisposition genes. Approximately one-third of patients had at least one variant of uncertain signficance (VUS) in this study, as has been reported in other series evaluating next generation sequencing panels. Most of these variants will eventually be reclassified, primarily as benign, but some will likely be pathogenic. VUSs should not be used to make clinical decisions.

NCCN continues to update medical management guidelines for highly penetrant genes and notably now include guidelines for moderate risk genes. For example, breast MRI screening is recommended for individuals with pathogenic variants in ATM and CHEK2. Although multigene panels can significantly aid in cancer risk management and expedite clinical translation of new genes, they equally have the potential to provide clinical misinformation and harm at the individual level if the data are not interpreted cautiously. Given the potential issues for patients and their families, gene panel testing for inherited cancer risk is recommended to be offered in conjunction with consultation with an experienced cancer genetic specialist (counselor or geneticist) as part of the testing process.