Chapter 23. Hereditary Gastrointestinal Cancer Syndromes

• Approximately 3–5% of colorectal cancers are caused by inherited gene mutations associated with hereditary nonpolyposis colorectal cancer (Lynch syndrome) or familial adenomatous polyposis.
• Genetic testing is clinically available for several hereditary gastrointestinal cancer syndromes and can be used to guide cancer screening recommendations.

The majority of cases of gastrointestinal cancer are believed to be sporadic events; however, inherited factors play a role in development of some tumors, with an estimated 5% being attributable to a single gene mutation. Hereditary gastrointestinal cancer syndromes convey a markedly increased risk for developing cancer and require specific strategies for diagnosis and management.

Identification of hereditary gastrointestinal cancer syndromes requires a thorough evaluation of patients' personal and family history of cancer. Clinical genetic testing can be useful in confirming the diagnosis of certain hereditary cancer syndromes and guiding cancer screening for family members. Tables 23–1 and 23–2 summarize clinical characteristics and cancer screening recommendations for the hereditary gastrointestinal cancer syndromes discussed in detail in this chapter.

Colorectal cancer (CRC) is the most common gastrointestinal malignancy, with more than 150,000 cases diagnosed each year in the United States. Although most CRC patients do not have a striking family history of CRC, approximately 30% report having one or more family members with a diagnosis of CRC. The lifetime risk of developing CRC is approximately 5% for the average American; however, individuals who have a first-degree relative with CRC have a twofold higher risk for developing colorectal neoplasia compared with individuals who have no family history of CRC. For individuals with numerous relatives with CRC, the cancer risk may be markedly higher; those who have inherited mutations in genes involved in mismatch repair or tumor suppression have a lifetime risk of CRC of 70–100% in the absence of medical intervention.

Identification of patients at risk for hereditary CRC syndromes relies on careful family history evaluation, because many individuals may not demonstrate a characteristic phenotype. Cancer risk stratification for every patient should involve eliciting a family history of cancers, including type of cancer and age of onset as well as family history of colorectal adenomas. Individuals whose family history includes multiple individuals with cancer, individuals diagnosed with two or more primary cancers, or with tumors diagnosed at young ages, should undergo more extensive family history evaluation of first-, second-, and third-degree relatives to determine whether there is evidence of an autosomal-dominant or autosomal-recessive pattern of inheritance.

Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary CRC syndrome and is estimated to account for 3–5% of CRC cases. This syndrome was first described by Dr Henry Lynch in families in which multiple cases of CRC were diagnosed at young ages. The original Lynch syndrome families were identified as having three or more cases of CRC with at least one diagnosed before age 50 years, as described by the Amsterdam criteria; however, additional studies have demonstrated that the cancer spectrum in these families includes other cancers, such as gastrointestinal, gynecologic, urinary tract, and sebaceous neoplasms of the skin. Because as many as 50% of families with Lynch syndrome do not meet the classic Amsterdam criteria, clinical diagnostic criteria have been expanded and modified to improve diagnostic sensitivity. As outlined by the Revised Bethesda guidelines (Table 23–3), Lynch syndrome should be suspected in families that have multiple relatives affected with CRC or related extracolonic tumors, or both, and in individuals who are diagnosed with CRC at a young age, have synchronous or metachronous colorectal cancers, or develop multiple Lynch-associated tumors. Figure 23–1 shows a pedigree of a family fulfilling criteria for Lynch syndrome.

Clinical Findings

Physical Features

CRC is usually the predominant cancer in most families with Lynch syndrome. Initial studies suggested that the mean age of onset of CRC is 44 years; however, there is wide variation in ages of diagnosis among families. Although colonic tumors in Lynch syndrome are often right-sided, many patients develop tumors in the left colon and rectum. Synchronous or metachronous tumors are common, and any individual diagnosed with two primary colon cancers warrants evaluation for Lynch syndrome. Although Lynch syndrome is also referred to as hereditary nonpolyposis colorectal cancer (HNPCC), most of the colorectal cancers do appear to arise from adenomatous polyps, although these polyps may be few in number and are often small and flat. The colorectal adenoma–carcinoma sequence appears to be accelerated in Lynch syndrome, and there are many reports of tumors arising within 3 years of a normal colonoscopy.

Endometrial (uterine) cancer is the second most common cancer described in Lynch syndrome families; however in some families, cases of endometrial cancers may outnumber CRC. Women with Lynch syndrome have a 40–60% lifetime risk for developing this malignancy, which is an unusual cancer in the general population. The lifetime risks for developing other Lynch-associated cancers, such as urinary tract cancers, ovarian cancer, and other gastrointestinal cancers (stomach, pancreas, small intestine), are also increased for individuals with Lynch syndrome and are estimated to be between 10% and 20%. Brain tumors (eg, glioblastomas and astrocytomas) have been described in the Turcot syndrome variant of Lynch syndrome. Cutaneous sebaceous adenomas and sebaceous carcinomas are rare skin tumors seen in the Muir-Torre variant, and it is currently recommended that any individual affected with sebaceous neoplasms of the skin undergo evaluation for Lynch syndrome regardless of his or her family history.

Genetic Features

The increased predisposition to developing cancer in Lynch syndrome is the result of autosomal dominantly inherited mutations in genes involved in DNA mismatch repair (MMR). Mutations in the genes hMLH1 and hMSH2 account for more than 80% of the identified MMR alterations in Lynch syndrome families. Mutations in the MMR gene hMSH6 have been identified in approximately 10% of Lynch syndrome families, and in hPMS2 in rare families. Recently, mutations in the gene TACSTD1/EPCAM, which regulates expression of MSH2, were also found in families with a clinical diagnosis of Lynch syndrome.

The protein products of MMR genes are involved in identifying and repairing errors that arise during DNA replication. In the setting of defective MMR gene function, these errors accumulate in segments of DNA containing repeated sequences known as microsatellites. DNA errors that disrupt the function of genes involved in growth regulation can lead to the development of tumors. Approximately 85% of the colorectal tumors in Lynch syndrome patients demonstrate high levels of microsatellite instability (MSI), a characteristic of defective MMR gene function. Immunohistochemical (IHC) analysis of colorectal tumors for expression of MMR proteins MLH1, MSH2, MSH6, and PMS2 frequently reveals loss of staining of the protein corresponding to the gene with the mutation. Since only 15% of sporadic CRC tumors demonstrate high levels of MSI, testing CRC tumors for MSI and loss of expression of MMR proteins has been proposed as a strategy to identify which patients with CRC may be at risk for Lynch syndrome and require additional genetic evaluation.

Approximately 60% of families that meet classic Amsterdam criteria are found to have germline mutations in one of the DNA MMR genes. However, recent studies suggest that classic Amsterdam families with multiple CRC diagnoses may include not only Lynch syndrome families, but also families with familial colorectal cancer syndrome X, which may or may not have a genetic basis. Like Lynch syndrome, familial colorectal cancer syndrome X families have multiple cases of CRC with apparent autosomal-dominant pattern of inheritance; however, the colorectal tumors in patients with familial colorectal cancer syndrome X do not have features of microsatellite instability and affected individuals do not appear to be at increased risk for extracolonic cancers.

Management

The high lifetime risk of colorectal and other extracolonic cancers, the accelerated progression of adenomas to adenocarcinomas, and the young age of onset of colorectal neoplasia require specialized strategies for cancer prevention.

Colorectal Cancer Screening

Individuals who are at risk for Lynch syndrome should begin having colonoscopies at age 20–25 years, with repeat examinations every 1–2 years. The need for a shorter interval between examinations became evident from European studies that demonstrated a reduction in CRC mortality for individuals who had colonoscopies every 3 years; however, cancers were still detected during that screening interval. The endoscopist should be vigilant for small or flat lesions, which may be associated with higher malignant potential in Lynch syndrome patients than in the general population.

Endometrial Cancer Screening

Expert panels recommend that women at risk for Lynch syndrome undergo endometrial cancer screening with annual transvaginal ultrasound and endometrial biopsy beginning at ages 30–35 years. At present, there are no data to support the efficacy of this endometrial cancer screening regimen, and women who have completed childbearing should be counseled to consider prophylactic hysterectomy as a more definitive measure to reduce their cancer risk.

Screening for Other Cancers

Although the risk for other extracolonic cancers is increased in Lynch syndrome, there is insufficient evidence to definitively recommend screening for many of these other cancers. For urinary tract cancer screening, annual urine cytology has been suggested, although its efficacy remains unproven. Screening for ovarian cancer includes transvaginal ultrasound and checking serum CA-125 levels once yearly. Screening for gastric cancer and small intestinal cancer using upper endoscopy has been proposed by some experts, but this has not been recommended by most guidelines. Individuals with Lynch syndrome from families with Muir-Torre should have annual dermatologic examinations to screen for cutaneous sebaceous neoplasms. At present, there are no recommendations for screening for pancreatic or central nervous system tumors because of lack of evidence to support effectiveness.

Prophylactic Surgery

Prophylactic surgery may be considered as an alternative to annual screening. For the majority of Lynch syndrome patients who are compliant with surveillance colonoscopies, prophylactic surgery is unlikely to be necessary. For some who develop early or multiple adenomas or for whom colonoscopy is painful, prophylactic colectomy may be a good option. Individuals who develop colorectal neoplasms requiring surgical resection should be offered extended resections with a subtotal colectomy, because the risk for metachronous lesions is high. Individuals who have had subtotal colectomies can then have screening of their residual colonic mucosa via flexible sigmoidoscopy.

Women should be counseled that there is limited evidence regarding the impact of endometrial screening on morbidity and mortality from endometrial cancer and that prophylactic hysterectomy and oophorectomy may be the most effective way to reduce risks of gynecologic cancer.

Clinical Genetic Testing

Genetic testing for MMR gene mutations associated with Lynch syndrome is increasingly available in clinical settings and provides the opportunity to confirm the diagnosis of Lynch syndrome in a family and to test other individuals in order to stratify their cancer risk. Cost-effectiveness models support the use of genetic testing for cancer risk stratification in Lynch syndrome families, and evidence suggests knowledge of a gene mutation makes individuals more likely to comply with the intense cancer screening required for cancer prevention.

The most efficient strategy for genetic testing is to begin the genetic evaluation with an individual who has a cancer diagnosis. For individuals who meet the Bethesda guidelines, the American Gastroenterological Association recommends starting with evaluation of a CRC tumor specimen to test for features of MSI and loss of staining for MLH1, MSH2, MSH6, and PMS2 proteins by IHC. As 85% of the CRC tumors in MMR gene mutation carriers demonstrate high levels of MSI or abnormal staining for MMR proteins, this pathologic testing can serve as a prescreening method to select individuals who should undergo germline testing for MMR mutations. Many clinical centers are implementing routine MSI and IHC testing for CRC tumors diagnosed in individuals age 50 and under, and some are advocating for universal tumor testing, as many cases of Lynch-associated CRC are diagnosed at age greater than 50 years.

For individuals who do not have a cancer diagnosis or tumor specimens available for MSI or IHC testing, there are risk assessment models that can be used to estimate the likelihood of Lynch syndrome. The PREMM(1,2,6) model is a Web-based clinical prediction rule that uses data from patients' personal and family history to estimate the probability that an individual carries a mutation in the MLH1, MSH2, or MSH6 genes (available from the Dana-Farber Cancer Institute, at http://www.dfci.org/premm). Individuals whose personal and family history produces a PREMM(1,2,6) model score of more than 5% should undergo additional evaluation for Lynch syndrome. MMRpro is another Web-based model that can be used for similar risk stratification to identify individuals who would benefit from genetic testing.

Clinical genetic testing for germline mutations in the MLH1, MSH2, MSH6, PMS2, and TACSTD1/EPCAM genes can be performed on DNA extracted from a peripheral blood sample. Clinical laboratories specializing in genetic testing perform full gene sequencing and southern blot analysis for large genomic deletions in these MMR genes. If testing reveals a pathogenic mutation in any of these genes, then testing is considered informative, and mutation-specific testing can be offered (at greatly reduced cost) to other family members to determine who has and has not inherited the genetic predisposition to cancer. If testing in a cancer-affected individual fails to reveal a mutation, then genetic testing is considered uninformative, and a clinical determination must be made about whether the suspicion for Lynch syndrome is sufficiently high to recommend Lynch syndrome cancer surveillance to all members of the family.

The high cost of commercial genetic testing for germline MMR mutations (at present, approximately U.S. $2000–$3000), the difficulties in interpreting and explaining uninformative genetic testing results, and the complexities of family dynamics are challenges in clinical genetic testing. The American Society for Clinical Oncology recommends that genetic testing be performed in conjunction with genetic counseling, which is available through most major cancer centers.

Familial Adenomatous Polyposis

Familial adenomatous polyposis (FAP) is the second most common inherited CRC syndrome. The classic FAP phenotype is one of hundreds to thousands of adenomatous polyps in the colon, with a nearly 100% risk of developing CRC by middle age if the affected individual's colon is not surgically removed. FAP accounts for approximately 1% of CRC cases. The incidence of FAP is approximately 1 in 10,000 persons. Although most cases arise in families with a known history through autosomal-dominant inheritance, approximately 30% of cases emerge as de novo gene mutations in the APC gene, and biallelic mutations in the base excision repair gene MYH can produce an autosomal-recessive inheritance pattern. Consequently, absence of a family history of polyposis does not exclude FAP.

Clinical Finding

Physical Features

Most individuals with classic familial polyposis develop numerous (hundreds to thousands) colorectal adenomas by the second or third decade of life. These adenomas are usually discovered during endoscopic evaluation for symptoms such as bleeding or diarrhea, or during routine screening in individuals with a known family history of FAP. Unfortunately, affected individuals who do not undergo early endoscopic evaluation and prophylactic colectomy often present with CRC by the fifth decade of life.

More than half of individuals affected with colonic polyposis develop adenomatous polyps in the upper gastrointestinal tract. After adenocarcinoma of the colorectum, duodenal and ampullary adenocarcinoma is the second leading cause of cancer death for FAP patients. Fundic gland polyps are common in the stomach; however, these are not known to have significant potential for malignant transformation.

Extracolonic malignancies associated with FAP include papillary thyroid cancer, adrenal carcinomas, and central nervous system tumors (Turcot syndrome). Children have an increased risk of developing hepatoblastomas and require screening with liver ultrasound scans and serum α-fetoprotein during the first 7 years of life. Intra-abdominal desmoid tumors can appear in some individuals with FAP, often arising after abdominal surgery. Although not considered malignancies, desmoid tumors can result in significant morbidity when they involve the mesentery and vasculature. Desmoid tumors define the Gardner syndrome variant of FAP and may be associated with mutations in a certain region of the APC gene.

Other physical findings associated with FAP include the presence of extra teeth, osteomas of the jaw and skull, and epidermoid cysts. Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is an ophthalmologic finding that should prompt evaluation for FAP.

Genetic Features

Most cases of FAP are caused by germline mutations in the adenomatous polyposis coli (APC) gene. Although most individuals with APC gene mutations inherited them from an affected parent, approximately one third of patients with FAP have new mutations in the APC gene and consequently do not have a family history of the disease.

The APC gene functions as a tumor suppressor. Loss of APC function in colonic epithelial cells is the first step toward neoplastic transformation, and somatic mutations in APC can be found in 80% of sporadic colon cancer tumors. Germline mutations in APC are believed to be highly penetrant, and most mutation carriers develop hundreds to thousands of colorectal adenomas.

Mutations in the APC gene are detected in more than 80% of patients with the classic FAP phenotype of hundreds to thousands of adenomas. Recent reports indicate that up to 30% of individuals with classic polyposis phenotypes without detectable APC mutations may have biallelic mutations in MYH, a base excision repair gene. Patients with MYH-associated polyposis can present with a similar phenotype to classic APC-associated FAP, but with an autosomal-recessive pattern of inheritance.

Management

Screening

Patients at risk of developing FAP should begin annual colorectal screening for polyps with flexible sigmoidoscopy or colonoscopy by age 11. Most affected individuals will develop colorectal adenomas during their teenage years or early twenties. Once colorectal adenomas are too numerous to be removed endoscopically, surgical removal of the colon is required. Total proctocolectomy with ileoanal anastomosis is the preferred operation. Other less-extensive surgeries, such as total colectomy with ileorectal anastomosis, leave some colonic mucosa behind that is at risk for neoplastic transformation and requires frequent endoscopies or use of chemo-preventive agents (eg, cyclooxygenase-2 [COX-2] inhibitors or sulindac) to control the growth of polyps.

Once patients are found to have colorectal adenomas, upper endoscopy is recommended to assess for adenomas in the duodenum and ampulla. A side-viewing upper endoscope should be used to examine the ampulla and perform biopsies. Duodenal or ampullary adenomas can be managed through endoscopic resection or medications (COX-2 inhibitors, sulindac) to reduce polyp burden. In rare cases, extensive adenomatous involvement, severe dysplasia, or adenocarcinoma is present, which requires surgical resection of the duodenum.

Patients with FAP are at increased risk for papillary thyroid cancer, and some guidelines recommend screening with annual thyroid examinations or thyroid ultrasound scans, or both.

Family members of individuals with FAP should be offered genetic testing for the gene mutation identified in the family in order to stratify their risk. In cases in which an individual does not undergo genetic testing or a genetic mutation cannot be identified in the family, at-risk family members should undergo colorectal screening with flexible sigmoidoscopy or colonoscopy every 1–2 years starting at age 10–12.

Clinical Genetic Testing

Genetic testing is now part of standard of care for risk stratification of family members of patients with a clinical diagnosis of FAP. Genetic evaluation should start with the proband with the polyposis phenotype, and should begin with testing for mutations in the APC gene. Full gene sequencing tests identify APC gene mutations in more than 80% of patients with classic polyposis phenotypes. If an APC mutation is not identified, then testing for biallelic mutations in the MYH gene may be considered. Y165C and G382D are the two most common mutations in the MYH gene found in individuals of western European ancestry. Full gene sequencing of MYH is performed for individuals who are found to have one of these two mutations or whose racial/ethnic ancestry is not western European. When genetic testing for APC and MYH in patients with classic polyposis fails to identify a genetic mutation, all family members must be considered at risk for developing FAP and should undergo colorectal screening as previously described.

Multiple Adenomas or Attenuated Adenomatous Polyposis

Individuals with 10–100 colorectal adenomas are considered to have a phenotype of multiple or attenuated polyposis. There is marked phenotypic and genotypic heterogeneity among patients with attenuated polyposis, and estimates of the risk of CRC vary widely, ranging from two times above population risk to as high as 80% for some patients. Some individuals with APC gene mutations in the 3′ or 5′ ends of the gene or with biallelic MYH mutations present with an attenuated polyposis phenotype, rather than with classic FAP. Current practice guidelines recommend genetic evaluation for patients with more than 20 colorectal adenomas; however, genetic testing for APC and MYH mutations is uninformative for many individuals with fewer than 100 adenomas, suggesting that other genetic or environmental factors may be involved in the pathogenesis.

Cancer prevention in patients with attenuated polyposis focuses on frequent endoscopic surveillance with polypectomies to clear the colonic mucosa of adenomas; if adenomas are too numerous or recur too quickly to be managed endoscopically, then surgical colectomy may be indicated. Individuals with attenuated polyposis may require colonoscopies every 1–2 years, with the option to increase or shorten the surveillance interval based on the rate of polyp growth. In cases of attenuated polyposis associated with an APC mutation, it is recommended that at-risk individuals follow FAP screening guidelines (see earlier discussion) as phenotypes may change over time and severity of polyposis can vary among family members. For individuals with biallelic MYH gene mutations, it is reasonable to begin colonoscopies and upper endoscopies early and repeat exams every 1–2 years, depending on the polyp burden. In cases in which genetic testing is uninformative, family members of affected individuals should begin colonoscopic screening 5–10 years younger than the age at which polyps appeared in the proband (or by age 40, whichever is earlier).

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (PJS) is characterized by multiple intestinal hamartomatous polyps; mucocutaneous pigmentation, which characteristically involves the lips; and a high lifetime risk of gastrointestinal, pancreatic, and breast cancers.

Clinical Findings

Physical Features

Individuals with PJS develop hamartomatous polyps throughout their gastrointestinal tract and can typically present with abdominal pain, stool that is positive for occult blood, obstruction, or intussusception. The clinical diagnosis of PJS can be made in individuals who have hamartomatous polyps and two of the following features: (1) labial melanin deposits, (2) small bowel polyps, or (3) family history of PJS.

PJS is also associated with increased risk for gastrointestinal cancers (colon, small intestine, stomach, pancreas), breast cancer, and sex cord tumors. Recent reports suggest patients with PJS have greater than 85% risk of developing cancer by age 70. Lifetime risks for colon, pancreatic, and breast cancers are estimated at 39%, 36%, and 54%, respectively.

Genetic Features

PJS demonstrates an autosomal-dominant pattern of inheritance. Mutations in STK-11, a serene/threonine kinase gene with tumor-suppressor function, have been found in approximately 70% of PJS patients. Research is ongoing to identify other genes that may be implicated in PJS patients.

Management

Patients with PJS require careful endoscopic surveillance for removal of polyps and screening for extraintestinal cancers. Recommendations include upper endoscopy, colonoscopy, and small bowel imaging (with small bowel series or capsule endoscopy) every 2–3 years, with removal of all polyps greater than 1–1.5 cm, which may require double-balloon enteroscopy or intraoperative enteroscopy. Women should have annual transvaginal ultrasound scans and serum CA-125 to screen for sex cord tumors and mammograms annually starting at age 25. Boys may be offered annual testicular ultrasound scans from ages 2–12 years. Recent studies have suggested that patients with PJS may benefit from pancreatic cancer screening with endoscopic ultrasound every 1–2 years.

Juvenile Polyposis

Juvenile polyposis is characterized by the appearance of multiple juvenile polyps and increased risk for gastrointestinal cancers.

Clinical Findings

Physical Features

Patients with juvenile polyposis typically have multiple (more than five) juvenile polyps and a family history of gastrointestinal cancer. Many affected individuals present with symptoms such as anemia, bleeding, or abdominal pain during childhood. There is also an association with cardiac abnormalities and other congenital anomalies. Patients are at increased risk for colorectal, gastric, duodenal, and pancreatic cancers, many of which appear at young ages.

Genetic Features

Juvenile polyposis has an autosomal-dominant pattern of inheritance. Mutations in the SMAD4 and BMPR1a genes, as well as in the PTEN gene, have been identified in some patients. Clinical genetic testing is available, but is often uninformative, because many affected individuals do not have detectable mutations.

Management

Patients with a family history of juvenile polyposis should undergo colorectal screening every 1–3 years starting at puberty. Affected individuals should have frequent upper endoscopy and colonoscopy for removal of polyps; in some cases, colectomy is required for management of polyp burden.

Cowden Syndrome

This hereditary syndrome is characterized by skin lesions (trichilemmomas), macrocephaly, and increased risk for breast, thyroid, and endometrial cancers. Cowden syndrome is associated with mutations in the PTEN gene. Although hamartomas of the gastrointestinal tract are described, the risk for gastrointestinal cancers does not appear to be as high for patients with Cowden syndrome as compared with other polyposis syndromes. However, recent data suggest there is some increase in risk for early-onset CRC, and early colonoscopic screening should be considered.

Hereditary Diffuse Gastric Cancer

Hereditary diffuse gastric cancer (HDGC) manifests as diffuse infiltrative adenocarcinoma of the stomach occurring in families in a pattern of autosomal-dominant inheritance, often affecting young individuals.

Clinical Findings

Physical Features

In contrast to most gastric cancers, which appear as ulcers or masses, diffuse gastric cancer usually presents as diffuse thickening of the stomach wall or linitis plastica, without an obvious endoscopic lesion. The International Gastric Cancer Linkage Consortium has defined HDGC as (1) two or more relatives with diffuse gastric cancer diagnosed before age 50 or (2) three or more relatives with diffuse gastric cancer diagnosed at any age. The lifetime risk of gastric cancer for individuals in these families has been estimated to be as high as 70%, and there are numerous reports of cancer diagnoses in individuals younger than 18 years of age. Studies have suggested there is also an increased risk of breast cancer in affected families.

Genetic Features

One third of families who meet criteria for HDGC have germline mutations in the E-cadherin/CDH1 tumor-suppressor gene. E-cadherin/CDH1 gene mutations were first identified in Maori families with gastric cancer in New Zealand. Genetic testing for HDGC is clinically available; however, it is informative in fewer than 50% of cases. If a pathogenic mutation is identified in a proband, testing can be offered to other family members.

Management

Prevention of gastric cancer among individuals at increased risk is challenging because endoscopic screening has been shown to have poor sensitivity for detecting diffuse gastric cancer. Consequently, prophylactic gastrectomy is recommended for mutation carriers and other patients at highest risk. Prophylactic gastrectomy carries with it considerable morbidity; however, expert panels have concluded that the 70% risk of developing gastric cancer among CDH1 mutation carriers justifies prophylactic gastrectomy. Given the increased risk of breast cancer among CDH1 mutation carriers, early screening with mammography or breast magnetic resonance imaging scan, or both, is recommended.

Familial Pancreatic Cancer

Although the vast majority of cases of pancreatic adenocarcinoma are sporadic, 3–10% seem to have a hereditary component. Risk varies from twofold to as high as 18–57-fold for families with two or three affected relatives. FPC is most often defined as families in which there are two or more first-degree relatives or three or more relatives with pancreatic adenocarcinoma.

Studies of FPC kindreds have identified pathogenic genetic mutations in approximately 20% of cases; thus, for the majority of families, a genetic cause of the pancreatic cancer cannot be found. FPC families may benefit from genetic evaluation for the following hereditary cancer syndromes:

Hereditary Breast/Ovarian Cancer (HBOC; BRCA1/BRCA2)

Mutations in the BRCA1 and BRCA2 genes account for the great majority of genetic mutations identified among pancreatic cancer families. Several studies have reported that prevalence of pancreatic cancer among families with HBOC is increased. The relative risk of developing pancreatic cancer for mutation carriers has been estimated as 2.26 for BRCA1 and 3.5–8 for BRCA2. In some HBOC families, the pancreatic cancer history overshadows the breast cancers. Consequently, it is recommended that evaluations for FPC begin with testing for mutations in BRCA1 and BRCA2.

Familial Atypical Multiple Mole Melanoma (FAMMM; P16/CDKN2A)

FAMMM is defined as more than 50 atypical nevi and malignant melanoma in two or more first- or second-degree relatives. Pancreatic cancer has been reported in nearly one fourth of FAMMM families. Many of these FAMMM families with pancreatic cancer appear to have germline mutations in the gene P16/CDKN2A (cyclin dependent kinase 2A). Carriers of a specific type of CDKN2A mutation appear to have a cumulative risk of pancreatic cancer of approximately 17% by age 75.

Peutz-Jeghers Syndrome

Individuals with PJS are most commonly characterized by their hamartomatous gastrointestinal polyps and mucocutaneous pigmentation, and approximately half are found to have germline mutations in the STK11 gene. In addition to conferring increased risk for breast cancer, PJS also confers an increased predisposition to pancreatic adenocarcinoma, with a lifetime risk of 36%.

Lynch Syndrome (HNPCC)

Pancreatic cancer is one of the gastrointestinal cancers that has been reported in HNPCC, and lifetime risk appears to be approximately 4% for MMR gene mutation carriers.

Hereditary Pancreatitis

Hereditary pancreatitis often presents as repeated episodes of pancreatic inflammation, ultimately resulting in chronic pancreatitis. In familial cases, there is evidence of autosomal-dominant inheritance, and mutations of the cationic trypsinogen gene (PRSS1) are found in 70% of kindreds. Mutations in the serene protease inhibitor Kazal 1 (SPINK1) gene have also been identified in some families. These mutations cause failure to inactivate trypsin, resulting in chronic pancreatitis, and confer a lifetime risk of pancreatic cancer of 40% by age 70.

PALB2

Mutations in the PALB2 gene have recently been identified in a small number of familial pancreatic cancer families. The PALB2 protein product binds to BRCA2, and PALB2 mutations have been described in association with inherited predisposition to breast cancer.

Management

Genetic counseling in patients with a genetic predisposition for pancreatic cancer should emphasize that in the majority of cases genetic testing does not reveal mutations in any of the genes known to be associated with pancreatic cancer. Advantages of pursuing genetic testing include the potential for identifying a mutation so that at-risk family members can undergo predisposition genetic testing and risk stratification. Also, identifying a mutation may affect cancer screening recommendations for the affected proband, as well as for the at-risk family members. Disadvantages include the fact that genetic testing may need to be repeated for many different genes, may be costly, and may not identify a genetic cause.

Patients with a family history of pancreatic cancer should be advised to stop cigarette smoking, as this has been found consistently to be an important risk factor for pancreatic cancer. At present, there is limited evidence that pancreatic cancer screening is effective in reducing morbidity and mortality from pancreatic cancer. Studies are ongoing to assess the utility of specialized pancreatic cancer screening for early detection and prevention of pancreatic cancer in individuals at increased risk; however, there are few data regarding which cystic lesions might have higher risk for neoplastic progression. However, experts have suggested considering pancreatic screening for patients in certain high-risk groups (such as those with PJS, those with two or more close relatives with pancreatic cancer, and BRCA2 mutation carriers with a family history of pancreatic cancer). Endoscopic ultrasound, helical computed tomography scanning, secretin-enhanced magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography have been used alone and in combination to try to detect abnormalities that may be precursors to pancreatic cancer, with the goal of timely pancreatic resection for high-risk lesions.