Genetic Testing in Gastrointestinal Cancers: A Case-Based Approach

OncologyONCOLOGY Vol 26 No 5
Volume 26
Issue 5

In this article, we use a case-based approach to focus on the hereditary aspects of the most common GI cancers, including pancreatic, gastric, and colon cancer.

High-risk genetic mutations that predispose individuals to various gastrointestinal (GI) cancers account for only about 5% of the population burden of these diseases. However, because early identification of at-risk individuals can so dramatically affect primary disease prevention, it is imperative that families who harbor susceptibility to these cancers be identified. The benefits of determining an underlying genetic susceptibility are important both for an individual patient’s ongoing management and for his or her family, where early identification of at-risk persons, along with the adoption of frequent cancer screenings and/or prophylactic risk-reduction surgeries, can have dramatic lifeprolonging benefits. In this article, we use a case-based approach to focus on the hereditary aspects of the most common GI cancers, including pancreatic, gastric, and colon cancer.

Be suspicious: knowing when to refer a patient for genetic testing

Indicators that identify individuals who may harbor germline mutations predisposing them to cancer include a family history of multiple cancers that reflect a pattern of disease, young age at onset, multiple primary tumors, tumors with particular histologic phenotypes, the presence of precursor lesions, and other related manifestations that cosegregate with cancer in the family. For individuals identified as being at risk for a cancer predisposition syndrome, referral to a genetic counselor for genetic risk assessment and testing is necessary and helps to ensure a comprehensive genetic evaluation. The investigation of a family for an underlying genetic cancer predisposition is guided by specific questions, including the type and age of cancer diagnoses in the family; whether there is access to pathology reports confirming the site of cancer and indicating histologic subtype; and in the scenario where the patient is unaffected, whether there is access to blood, tissue, or stored DNA from an affected family member on which genetic testing can be performed.

Typically, genetic testing should begin with the individual in the family most likely to be affected with the cancer predisposition syndrome, ie, with the family member who has the most severe disease, earliest onset, or rarest phenotype. Testing this individual decreases the likelihood of testing a family member with a phenocopy (eg, colon cancer that occurred sporadically) and is typically the most informative approach.

Which cancers have a hereditary component?

Familial clustering, evident in many cancer types, can in part be attributed to shared environmental exposures as well as to genetic susceptibility conferred by low-, medium-, or high-risk inherited factors. The heritable component of disease can be measured through studies comparing rates of disease in monozygotic vs dizygotic twins. In the case of cancer, an increased heritability has been shown for a variety of cancers, including prostate, colorectal, and breast cancers.[1] Further evidence for increased heritability can be ascertained from epidemiologic studies using cancer data from homogenous populations that show greater than expected observed rates of certain types of cancer within families.[2] In the case of families with multiple affected individuals in subsequent generations, there is heightened suspicion for rare mutations in genes that confer a high risk of cancer. In families where the pattern is not as striking, the cancer predisposition may still be genetic in origin but could be due to lower-penetrance risk variants. Genome-wide association studies have uncovered common risk variants in the genome that confer susceptibility to certain types of cancer[3]; however, independently, each of these low-risk variants only marginally increases a person’s risk of cancer above that of the general population. Multiplicative models of common risk variants could potentially explain a proportion of familial clustering or be used to modify risk within moderate- to high-risk pedigrees, but as of yet, the clinical utility of redefining risk based on common variation has not been demonstrated.


General Considerations in the Genetic Risk Assessment of Hereditary Cancers

To date, a large portion of the genetic etiology of hereditary cancer predisposition remains unexplained; even many seemingly high-risk families will not have an identifiable mutation in known cancer predisposition genes. However, with current technological advances in sequencing, rather than testing an individual for a specific gene or genes, clinical genetic testing may eventually evolve to incorporate whole-exome or whole-genome testing, in which all genes are assessed and the culprit genetic changes are identified after testing. Theoretically, this could reveal high-, medium-, and low-risk factors that might contribute to a familial cancer in an individual. In addition, factors such as genetic background and epigenetics (changes not encoded in the genome, resulting instead from environmental exposures that influence gene expression) may also further influence disease penetrance and affect an individual’s cancer risk.

To illustrate the benefits of genetic testing in individuals with a hereditary predisposition to GI cancers, we have provided four scenarios that are typical of what is encountered in the clinic. For each case, the general considerations outlined in Table 1 should be taken into account during the genetic risk assessment process.

Familial Pancreatic Cancer


Pedigree of Mr. X’s Family

Case: Mr. X is a 58-year-old man with a recent diagnosis of metastatic pancreatic cancer. On review of family history, you find a history of pancreatic, breast, and prostate cancers on the maternal side of the family (Figure 1). There is no personal or family history of melanoma, and on examination of his skin you do not find perioral freckling, melanomatous lesions, or evidence of old skin surgeries.

Based on the recently updated National Comprehensive Cancer Network (NCCN) guidelines,[4] hereditary breast ovarian cancer (HBOC) syndrome should be considered in individuals with pancreatic adenocarcinoma diagnosed at any age who have two or more close relatives with breast and/or ovarian and/or pancreatic cancer diagnosed at any age. Thus, after a discussion with the patient regarding the potential usefulness to him and his family members of identifying an inherited mutation, you refer the patient to clinical genetics for further discussion of genetic testing.


Familial Pancreatic Cancer

Genetic evaluation: A total of 43,920 new diagnoses of pancreatic cancer in US men and women is projected for 2012.[5] A quarter of these will prove to be secondary to environmental factors such as smoking; however, roughly 4,392 individuals (10%) will prove to have familial clustering of the disease, with 2% having disease resulting from a mutation in a high-risk Mendelian susceptibility gene (Figure 2).

In view of Mr. X’s family history of pancreatic, breast, and prostate cancers, HBOC syndrome is considered. The BRCA2 cancer susceptibility gene has been shown to be associated with sporadic and familial pancreatic cancer,[6,7] with the Breast Cancer Linkage Consortium study and other studies observing a 3.5- to 7-fold increased risk of pancreatic cancer in families carrying a BRCA2 mutation.[8,9] In patients with familial pancreatic cancer, a BRCA2 mutation is identified in 11% to 17% of families.[7,10] The association between BRCA1 mutations and pancreatic cancer is not as well defined, but the relative risk of pancreatic cancer in BRCA1 mutation carriers has been estimated to be two-fold higher than in the general population.[11]

It is notable that mutations in the BRCA1/2 genes, while rare in the general population, are more prevalent in certain ethnic groups, such as Ashkenazi Jews. Since Mr. X is of Ashkenazi Jewish ancestry, testing begins with evaluation for the three Ashkenazi founder mutations, which account for ~90% to 95% of BRCA mutations in the Ashkenazim. Genetic testing reveals the presence of the BRCA2 6174delT germline mutation, the most common Ashkenazi founder mutation.[12] In patients of Ashkenazi ancestry (unselected for family history) with resected pancreatic cancer, 5.5% were found to harbor a BRCA founder mutation, and in Ashkenazi breast-pancreas families, 14.2% were BRCA mutation–positive, with nearly equal distribution of BRCA1 and BRCA2 mutation carriers, suggesting that both of these genes may be involved with pancreatic cancer risk.[13,14]

During the genetic assessment of patients with pancreatic cancer, a number of other hereditary pancreatic cancer predispositions may also be considered (Figure 2). Peutz-Jeghers syndrome,[15] which has a relative risk of 132 for pancreatic cancer,[16] is usually associated with a history of intestinal polyposis and often presents with intussusception, gastrointestinal bleeding, and/or perioral freckling. Familial adenomatous polyposis, which has a relative risk of 4.5 for pancreatic cancer,[17] is associated with a history of colorectal polyps or colorectal cancer; extraintestinal features such as congenital hypertrophy of the retinal pigment epithelium; or extracolonic tumors, such as pediatric hepatoblastomas, sebaceous adenomas, osteomas, desmoids, or medulloblastomas. Lynch syndrome has a ~9-fold increase in risk for pancreatic cancer above that of the general population[18]; a history of colorectal, endometrial, and other cancers can also usually be found. Familial atypical multiple mole melanoma (FAMMM) syndrome, associated with germline mutations in CDKN2A, has a relative risk of 13 to 22 for pancreatic cancer, and is generally associated with a history of melanomas or dysplastic nevi.[19] In addition, PALB2 mutations, thought to be associated with both breast and pancreatic cancer susceptibility, may also be considered.[20-22] Furthermore, other very rare conditions can be associated with an increased risk of pancreatic cancer, including hereditary pancreatitis, which has a relative risk of 53 to 87 for pancreatic cancer (Table).[23-25]


Genes and Their Respective Syndromes That Are Associated WIth Familial Pancreatic Cancer

In terms of oncologic treatment, identification of a BRCA mutation in a patient with pancreatic cancer is becoming increasingly important, since new therapies, such as poly(ADP-ribose) polymerase (PARP) inhibitors, have shown significant activity in patients with advanced BRCA-associated breast and ovarian cancers and hold potential for the treatment of BRCA-associated pancreatic cancer as well.[26] In fact, clinical trials exploring the efficacy of PARP inhibitors in BRCA-associated pancreatic cancer are currently underway.

With the knowledge that a BRCA mutation has been identified in this patient, cascade testing of family members can be performed so that at-risk family members can undertake the recommended cancer screening and prevention strategies outlined in Table 2. Although pancreatic cancer screening studies to date have not demonstrated a decrease in pancreatic cancer mortality, participation in clinical trials assessing the efficacy of pancreatic cancer screening in high-risk individuals may be a consideration for some BRCA-positive families with a history of pancreatic cancer.

Family History of Gastric Cancer


Pedigree of Miss Y's Family

Case: Miss Y is a healthy 20-year-old woman referred to you for gastroscopy screening because of a family history of diffuse gastric cancer (DGC) in her father and paternal uncle. You schedule her for an endoscopy and refer her to genetics. In the interim, results of Miss Y’s gastroscopy are negative. Given her family history of a lobular breast cancer diagnosis in her paternal aunt at age 55 years and the two diagnoses of DGC in her father at age 35 years and in her paternal uncle at age 50 years (Figure 3), you refer her for genetic counseling.

Genetic evaluation: A total of 21,320 new diagnoses of gastric cancer in US men and women is projected for 2012.[5] Approximately 3198 of these newly diagnosed patients (15%) will prove to have familial clustering of the disease, and in 852 (4%), the diagnosis will be due to high-risk Mendelian susceptibility genes (Figure 4).


Familial Gastric Cancer

This particular case is highly suspicious for hereditary DGC (HDGC), associated with germline mutations in CDH1, which encodes a cell-cell adhesion molecule (E-cadherin) and is the only gene associated with the syndrome.[27] Because Miss Y’s father and paternal uncle are deceased, testing of CDH1 is initiated in her paternal aunt who had lobular breast cancer. Even though this aunt’s cancer could potentially be a phenocopy (sporadic breast cancer unrelated to disease), because lobular breast cancer is associated with HDGC, she is the appropriate individual to test. Point mutations in CDH1 are found in 30% to 50% of HDGC families, with deletions in the CDH1 gene accounting for an additional 4% of such families.[28] In this case, sequencing reveals a germline frameshift mutation in CDH1 that has previously been reported in an unrelated HDGC family.

In view of the known mutation in the family, Miss Y can now be tested to determine her carrier status. Prior to genetic testing, she is counseled with regard to HDGC, its current management, and the benefits and limitations of genetic testing. It is discussed that a genetic result would help clarify her risk and therefore might aid her decision making around surveillance and preventive interventions. While it is known that virtually all carriers of CDH1 mutations have or will develop minute cancers within the lining of their stomachs, 20% of mutation carriers will not develop clinically significant DGC. What triggers the progression to clinically significant DGC is not known. Unfortunately, there is no effective means by which to find or monitor these lesions; therefore, the only way to reduce risk of DGC is by completely removing the stomach, which has significant associated morbidity and a 1% risk of mortality. Although there is a federal law prohibiting health care and employment discrimination, the potential for insurance discrimination, as well as the possible psychological implications for both the patient and the family, is discussed-as is done in every pretest counseling session. Based on her family history, Miss Y has a 50% chance of inheriting the mutation, since it is assumed that her father with DGC is an obligate carrier who shares the familial CDH1 mutation.

Following the pretest counseling, Miss Y undertakes predictive genetic testing for the familial mutation. The results indicate that Miss Y is positive for the mutation; she therefore is counseled regarding her 80% lifetime risk of DGC and 60% lifetime risk of lobular breast cancer,[29] as well as with regard to the recommended screening. Currently, the International Gastric Cancer Linkage Consortium (IGCLC) recommends annual upper endoscopies with multiple random biopsies for gastric cancer surveillance until prophylactic total gastrectomy is undertaken.[29] Multiple (minimum of 30) gastric biopsies must be taken randomly in order to increase the chance of detection.[29,30] Miss Y is referred to a multidisciplinary team for further discussion regarding total prophylactic gastrectomy. She ends up deciding to delay the procedure and continue with endoscopic surveillance until she has completed child bearing. It should be noted, however, that there are case reports of successful pregnancies post–prophylactic gastrectomy.[31] It is important to bear in mind that the timing of prophylactic gastrectomy is a highly individual decision that the patient should make with the help of a multidisciplinary team that includes a gastroenterologist, a geneticist, a genetic counselor, a surgeon, a nutritionist, and an oncologist, as well as a psychologist/counselor.


A Selection of Other Genes That Can Have Gastrointestinal Manifestations, WIth Their Respective Syndromes

Miss Y discusses her mutation results with her sister. Her sister is keen to learn more information; however, her insurance provider is unwilling to cover the costs of genetic counseling and testing. In general, insurance providers differ in their specific policies regarding genetic counseling and testing; thus, it is worthwhile for a patient to investigate the policies of several companies. Alternatively, these services can be privately paid for-and for privacy concerns, some individuals elect this option. In the case of Miss Y’s sister, testing should be considered medically necessary. She has a 50% chance of having inherited a previously identified familial mutation associated with a highly penetrant cancer susceptibility syndrome for which surveillance has been shown to miss underlying cancer. It thus is reasonable for the ordering physician to appeal to the insurance provider on behalf of the patient to provide coverage for genetic counseling and testing. It should be emphasized that without being able to redefine the patient’s genetic risk, the insurance provider would by default need to cover the medically necessary and recommended surveillance for an at-risk individual from an HDGC family. In general, enrolling patients into disease-specific research studies is important to advance ongoing research and understanding of the disease. In some cases it is possible for study participants to learn preliminary genetic testing research results.

Following an appeal to the insurer for targeted testing for the family mutation, Miss Y’s sister is found not to be a carrier. Based on these results, Miss Y’s sister’s risk for gastric and breast cancer returns to that of the general population, and she does not require high-risk gastric or breast cancer surveillance (Table 3).

Early-Onset Colon Cancer


Pedigree of Mrs. V's Family

Case: Mrs. V is a 44-year-old woman referred by her gastroenterologist because of a new diagnosis of right-sided colorectal cancer (CRC) diagnosed on colonoscopy performed secondary to rectal bleeding. Review of the family history reveals that her maternal grandmother had uterine cancer at age 50 years and her maternal uncle had CRC at age 50 years (Figure 5). In view of the patient’s younger age at onset[5] and the family history of Lynch syndrome–related cancers, an underlying genetic susceptibility needs to be investigated.

Genetic evaluation: A total of 143,460 new diagnoses of CRC in US men and women is projected for 2012.[5] Approximately 21,519 of these newly diagnosed patients (15%) will prove to have familial clustering of the disease, and in 7173 (5%), the diagnosis will be the result of a mutation in a high-risk Mendelian susceptibility gene. Specifically, Lynch syndrome, caused by mutations in the DNA mismatch repair (MMR) genes, accounts for 2% to 5% of all CRC (Figure 6).


Familial Colon Cancer

Even without the family history of Lynch syndrome–related cancers, Mrs. V meets the revised Bethesda guidelines criteria for consideration of a diagnosis of Lynch syndrome (on the basis of a diagnosis of CRC under the age of 50 [Table 2]). The NCCN, in the revised Bethesda guidelines, recommends further examination of the tumor with either microsatellite testing and/or immunohistochemistry.[32] Lynch syndrome is an autosomal dominant cancer susceptibility syndrome caused by mutations in one of several DNA MMR genes (or a gene located nearby) that ultimately lead to loss or abnormal function of the MMR proteins (Table 2). Alterations in the MMR system cause errors in DNA replication to accumulate, particularly in sequences of DNA known as microsatellites. These repetitive regions of DNA easily mispair during normal DNA replication, causing gains or losses of the repeat sequences. If the MMR proteins are impaired, the cell cannot properly repair its DNA, resulting in the accumulation of microsatellite instability (MSI). In patients with a germline MMR gene mutation, a second copy of the affected MMR gene is somatically mutated, with progressive accumulation of altered microsatellites in the coding regions of genes involved in tumor initiation and progression.

Individuals with Lynch syndrome develop cancers in certain tissues that are more susceptible to losing the function of particular proteins; thus, there is a distinct pattern of cancers that is associated with the syndrome (Table 2). The optimal way to screen a cancer patient for Lynch syndrome is via tumor tissue testing. Analysis for the presence of MSI and/or immunohistochemical staining (IHC) for the four MMR proteins can be performed on colon and endometrial tumors. In patients with tumors exhibiting defective MMR either by MSI testing or by IHC, further germline genetic testing for the appropriate MMR genes is indicated. Complicating the diagnosis of Lynch syndrome is the fact that 15% to 20% of sporadic colon and endometrial cancers exhibit the same MMR repair defects as their hereditary counterparts.[33] Thus, the results of tumor testing need to be interpreted in conjunction with other clinical information. For example, when MLH1 protein is deficient in the tumor, as determined by IHC, it is possible either that there is an MLH1 germline mutation or that somatic epigenetic silencing has occurred. In such cases, testing for the presence of MLH1 promoter hypermethylation or the presence of a V600E mutation in BRAF, either of which would identify the tumor as sporadic, can help rule out Lynch syndrome.[34] Keep in mind that although MSI and IHC testing are useful screens, they are not 100% sensitive. The sensitivity of MSI testing is related to the panel of microsatellite markers used. While there have been efforts to standardize them, the panels can differ between institutions.[35] When using 3 or more single-nucleotide repeating microsatellites, the sensitivity for detecting germline MLH1 and MSH2 mutations is 89%, and 77% for MSH6; the sensitivity of IHC for MLH1, MSH2, and MSH6 is 83%.[36] Because either approach can theoretically lead to false-negative assessments for Lynch syndrome and thus potentially result in missed opportunities for surveillance and risk-reducing strategies, if there is sufficient clinical suspicion of Lynch syndrome based on personal or family history or other clinical parameters, the case for further genetic testing should be made. For example, because some tumors in patients with Lynch syndrome are missed by MSI testing but detected by IHC and vice versa, a gain in sensitivity may be achieved by the use of both tests and is advisable in high-risk clinical scenarios.

Patients with a diagnosis of Lynch syndrome have a 50% to 80% lifetime risk of CRC, with an associated accelerated progression of the adenoma-to-carcinoma sequence and a mean age of 45 years at CRC diagnosis in the proband (although diagnosis is generally later in the mutation-carrier family members).[37,38] Women with Lynch syndrome are also at a substantially increased risk for endometrial cancer, with an estimated lifetime risk of 40% to 60%.[39,40] Other Lynch syndrome–associated cancers include cancers of the stomach, small intestine, pancreas, ovaries, and biliary tract, and urothelial carcinoma of the renal pelvis and ureter. The presence of sebaceous neoplasms of the skin is seen in Muir-Torre syndrome, a variant of Lynch syndrome, while brain tumors, including glioblastomas and astrocytomas, are seen in Lynch families with Turcot syndrome.

Given her early age at onset and her family history of Lynch-associated cancers, Mrs. V’s colon tumor biopsy tissue was assessed by IHC for expression of the four DNA MMR proteins. An intact expression of MLH1 and PMS2 proteins was noted; however, staining was absent for the expression of both MSH2 and MSH6 proteins. IHC may be helpful in the diagnosis of Lynch syndrome, as results may direct gene-specific clinical genetic testing. In this case, the absence of MSH2/MSH6 protein expression suggested that the most likely culprit gene was MSH2. Thus, Mrs. V underwent germline genetic testing with sequencing, which revealed a deleterious mutation in the MSH2 gene.

In patients with a new diagnosis of colorectal cancer, the upfront identification of Lynch syndrome may have a significant impact on surgical management. First, given the high risk of metachronous colorectal cancer[41] (16% at 10 years, 40% at 20 years after initial CRC diagnosis[42]), subtotal colectomy as opposed to a segmental colon resection may be considered. Subtotal colectomy reduces the metachronous risk by 31% for every 10 cms of bowel removed.[42] Given the associated increased lifetime risk of endometrial and ovarian cancer, if a female patient has completed childbearing, a prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH-BSO) may also be considered. After the presurgical clinical genetics evaluation and the identification of Lynch syndrome, Mrs. V underwent subtotal colectomy as well as risk-reducing TAH-BSO. Had Mrs. V elected not to undergo subtotal colectomy, following treatment and follow-up surveillance for her primary CRC, she would have been advised to adhere to recommendations for surveillance by colonoscopy every 1 to 2 years.[43]

It is notable that colorectal cancers exhibiting defective MMR, whether due to a somatic event or a germline MMR mutation, exhibit certain phenotypic features. Consistent with a Lynch syndrome–associated CRC, Mrs. V’s pathology revealed a right-sided, poorly-differentiated, mucinous invasive adenocarcinoma with medullary features and the presence of tumor-infiltrating lymphocytes.[44,45] More recent evidence also suggests that defective MMR (ie, the MSI-high tumor phenotype) may also be a prognostic and a predictive marker in CRC. Numerous retrospective studies, including large meta-analyses, have shown that patients with CRC with defective MMR have improved stage-independent survival compared with patients with proficient-MMR CRC.[45,46] In addition, by using data from randomized clinical trials of fluorouracil (5-FU)-based therapy vs surgery-only controls, a predictive role for MMR status has also been demonstrated, with CRC patients who have defective MMR not appearing to benefit from treatment with 5-FU–based chemotherapy.[47,48]

Last but not least, with the identification of a germline MSH2 mutation in this patient, targeted genetic testing can now be undertaken in her family members, and at-risk family members can partake in appropriate cancer screening and prevention measures (Table 2).[32]

Colon Cancer in the Setting of Polyposis

Case: Mrs. W is a 64-year-old woman with a past history of multiple colon polyps who underwent diagnostic colonoscopy because of anemia. Colonoscopy revealed an ulcerated cecal tumor, with biopsy confirming a moderately differentiated invasive adenocarcinoma. At 50 years of age, initial screening colonoscopy had revealed multiple polyps of differing types: six tubular adenomas, one villous adenoma, and three hyperplastic polyps. Subsequent intermittent colonoscopies identified several polyps each time. At 58 years of age, she was found to have a large villous adenoma requiring a segmental resection of the transverse colon. In light of her history of polyposis and colon cancer, you refer her to genetics.


Pedigree of Mrs. W's Family

Genetics evaluation: Apart from her mother’s history of a solitary polyp, there is no other known history of polyps in the family (Figure 7). Syndromes in which there is a predisposition for fewer than 100 adenomatous polyps include the autosomal dominant syndrome of attentuated familial adenomatous polyposis (AFAP) and the recessive syndrome of MYH-associated polyposis (MAP). Because of her history of cecal cancer, Lynch syndrome is also in the differential diagnosis. If there had been more than 100 polyps, familial adenomatous polyposis (FAP) would have been more likely, and if the polyps had not been defined, one might have considered looking for signs of other polyposis conditions, such as Peutz-Jeghers, Cowden syndrome, juvenile polyposis, neurofibromatosis, multiple endocrine neoplasia type I, and tuberous sclerosis.

FAP is an autosomal dominant syndrome that occurs in 1 of every 7000 to 22,000 individuals and is caused by germline mutations in the APC gene.[49] Twenty-five percent of mutations are de novo,[49] while a small fraction of cases result from somatic mosaicism,[50] explaining the lack of family history in a proportion of cases. The classic syndrome is characterized by adenomatous polyps carpeting the colon by young adulthood,[51] with the risk of colorectal cancer being virtually 100% (mean age at diagnosis, 40 years). Screening recommendations for classic FAP include annual flexible sigmoidoscopy beginning at age 10 to 15 years-or earlier if symptoms develop. Once polyps are identified, it is recommended that screening be switched to colonoscopy. For classic FAP, prophylactic colectomy is the treatment of choice. Upper gastrointestinal polyposis in FAP is common. Fundic gland polyps occur in the stomach and show focal dysplasia.[52] Although uncommon, there are reports of gastric cancer associated with FAP.[53,54] There is also a 95% risk of duodenal polyps, with an associated 5% risk of malignant progression.[55] When studied in a prospective manner, surveillance for duodenal adenocarcinoma and subsequent early referral for curative surgery does not demonstrate efficacy[55]; thus, recommendations exist for prophylactic surgery, dependent on the polyp burden.[32]

Other cancers associated with the syndrome include pancreatic, papillary thyroid, biliary tract, and brain (usually medulloblastoma)-and in children there is a risk of hepatoblastoma. Other benign extraintestinal manifestations include fibromas, lipomas, sebaceous and epidermoid cysts, nasopharyngeal angiofibromas, osteomas of the jaw, desmoid tumors, dental anomalies, and congenital hypertrophy of the retinal pigment epithelium [56].

Variations of classical FAP include AFAP, which is usually caused by mutations in the 3' or 5' regions of the APC gene, and which either gives rise to fewer polyps (< 100) or has a later age at onset of polyposis. AFAP rarely displays the extraintestinal manifestations of FAP. The average age for CRC in AFAP is 54 years.[57]

Mrs. W was tested for germline APC mutations and was found to be negative by sequencing and rearrangement testing. Subsequently, she was tested for biallelic mutations in MUTYH and was found to be positive. MYH-associated polyposis is inherited in an autosomal recessive manner. Thus far, the reported spectrum of disease has been mainly confined to the colon and upper gastrointestinal tract, where duodenal polyposis occurs relatively frequently. Recom-mendations for screening include colonoscopy beginning at age 25 to 30 years and repeated every 3 to 5 years until polyps are detected. Once adenomatous polyps are identified, the colonoscopy and polypectomy surveillance intervals are decreased to every 1 to 2 years. In order to detect duodenal malignancy, upper endoscopy with side viewing of the duodenum should be performed every 3 to 5 years beginning at age 30 to 35 years.[32] With regard to other potential cancers, the full spectrum of disease is still being defined. Prophylactic colectomy is undertaken depending on patient age, disease location, and polyp burden.

Mrs. W’s clinical picture could easily have been classified as AFAP, which has a 50% chance of being passed to each of her children. Fortunately, genetic testing revealed the underlying cause to be MAP, which is autosomal recessive. This means that her children will be obligate carriers of either one of her MYH mutations; however, the chance that they would be affected by the syndrome is very low-less than 1%, based on an MYH mutation–carrier frequency of 1% to 2% in the general population. While still not completely elucidated, the risk of CRC in monoallelic MYH mutation carriers may be moderately increased.[58] This case demonstrates that in APC-negative polyposis cases, an evaluation for MYH mutations should be pursued. Moreover, when unselected APC-negative index cases of FAP or AFAP were screened, regardless of polyposis subtype (typical, atypical, attenuated), the detection rate for biallelic MYH mutations was significant-17% (55 of 329 patients), and even higher ( 27%) when the denominator included only cases with the attenuated phenotype.[58] In general, the feature that more often characterized cases as attenuated was older age at onset and not necessarily a lower number of polyps.[58]

It was recently shown that homozygous BUB1B mutations previously thought to cause only the rare multivariegated aneuploidy syndrome (characterized by microcephaly, intellectual disability, and predisposition to multiple solid and hematologic cancers), predisposed a healthy adult to gastrointestinal polyps and colorectal cancer.[59] Detection of the patient’s underlying syndrome was only possible by karyotype analysis, which demonstrated mosaic aneuploidies, structural rearrangements, and premature chromatid separation secondary to the patient’s underlying genetic defect in mitosis. Investigation of these phenomena requires karyotype analysis of dividing cells and therefore can be performed using lymphocytes from blood, or alternatively, skin fibroblasts.[59]

Future Directions

In this review, we have focused on the strategy of targeted testing of genes known to be associated with particular gastrointestinal malignancies. This has been proven to be an effective strategy and has enabled the implementation of surveillance and life-prolonging risk-reduction surgeries in those at highest risk. However, clinical genetics is changing. Along with the advent of cheaper sequencing technologies will come the era of personalized medicine, which will give rise to the discovery of new cancer predisposition genes and the rediscovery of known genes, either in milder forms of the classic disease or in different roles. Thus, the unknown portions of the familial clustering wedges that are currently unaccounted for will start to fill. Furthermore, as we gain a higher-resolution picture of rare genetic events through sequencing of individuals or families, the collective impact of the rare variants and the common low-risk variants found in genome-wide association studies may explain the variable presentations seen within and between families.

Just as important as identifying a patient’s germline susceptibility is the ability to use that information to help the patient and his or her family make decisions about management, surveillance, and potential interventions. The information we give patients depends on our knowledge of the natural history of the cancer syndromes; therefore, recruitment into research protocols continues to be essential. Such research will allow us to capture the genotype-phenotype correlations that will help us determine the triggers of hereditary cancer and improve risk stratification within affected families.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.



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