Curr Probl Cancer 38 (2014) 249–261

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Hereditary colorectal cancer: More common than you think Kory W. Jasperson, MS, CGC

Introduction It is estimated that more than 20% of all colorectal cancers (CRCs) have a familial component, and up to 6% of cases are due to a known high-risk hereditary syndrome.1 It is imperative that health care providers keep abreast of the genetics of CRC, as 1 in 5 patients with CRC walking through their office door may need referral for genetic counseling. Despite the well-documented benefits of increased screening and risk-reducing interventions in hereditary CRC syndromes, many remain undiagnosed. Reviewed here are novel and proven strategies to identify patients at risk for hereditary CRC syndromes, with a focus on Lynch syndrome (LS) and universal tumor testing of all CRCs, familial adenomatous polyposis (FAP), and MUTYH-associated polyposis (MAP). In addition, a case-based approach is used to highlight diagnostic pitfalls and successful interventions, including early cancer detection and prevention opportunities in families affected by a hereditary CRC syndrome.

Case 1 An otherwise healthy 54-year-old woman presents with a 2-month history of postmenopausal vaginal bleeding. She subsequently is diagnosed with stage IIA endometrial cancer (EC) and undergoes a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The hospital at which she was diagnosed recently implemented a testing protocol to routinely evaluate all ECs for LS. This testing protocol includes immunohistochemistry (IHC) analysis using MLH1, MSH2, MSH6, and PMS2 antibody staining on all surgically resected ECs, regardless of the age of onset or family history (this is also referred to as universal tumor testing). IHC analysis revealed absent MSH6 staining and normal staining of MLH1, MSH2, and PMS2. Given the abnormal IHC result, the patient was referred for genetic counseling and testing. Cancer risk assessment and testing During her genetic counseling appointment, a detailed family history was obtained as outlined in Figure 1. Her 59-year-old sister was diagnosed with ovarian cancer at the age of 58 years. This sister had undergone comprehensive BRCA1 and BRCA2 genetic testing the previous year, and no mutations http://dx.doi.org/10.1016/j.currproblcancer.2014.10.005 0147-0272/& 2014 Elsevier Inc. All rights reserved.

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Fig. 1. Personal and family history of cancer and genetic test results for case 1 with Lynch syndrome.

were identified. The remainder of the family history was unremarkable, though her father died in an auto accident at a young age. In addition, he was adopted, and no information was available regarding his side of the family. Owing to the patient’s abnormal IHC test result, genetic testing of the MSH6 gene was performed. This revealed a deleterious mutation, confirming a diagnosis of LS in the patient. Additionally, genetic testing for the known MSH6 mutation was offered to her at-risk relatives, including her siblings and children. The results and implications of further testing in this family are outlined in the following sections. Familial implications The patient underwent a screening colonoscopy 4 years ago at the age of 50 years, and no polyps were found. The typical recommendation would have been for her to undergo a followup colonoscopy in 10 years. However, given her new diagnosis of LS, a repeat colonoscopy was performed, and she was found to have a stage IA cecal mucinous adenocarcinoma. She was recommended to undergo right hemicolectomy but was also given the option of total colectomy with ileorectal anastomosis owing to the increased risk of metachronous CRC in LS. She elected total colectomy with ileorectal anastomosis. Lynch syndrome LS, also known as hereditary nonpolyposis colorectal cancer, is an autosomal dominant condition caused by a germline mutation in one of the mismatch repair genes (MLH1, MSH2,

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MSH6, and PMS2) or the EPCAM gene.1 LS is associated with a high risk of CRC and EC, though the risks vary depending on the causative gene. For example, MLH1 and MSH2 mutation carriers have up to an 80% risk of CRC and a 60% risk of EC, whereas individuals with PMS2 mutations have a much lower lifetime risk for CRC (15%-20%) and EC (15%).2-4 The risk for various other cancers is also significantly increased in LS, including but not limited to ovarian, gastric, small bowel, ureter, renal pelvis, glioblastoma, and pancreas cancers (Table 1).2 Breast and prostate cancers have also been linked to LS, though these are not considered characteristic LS malignancies.5 LS is responsible for 1 of every 35 cases of CRC.6 Not only is LS the most common cause of hereditary CRC, it is also responsible for approximately 2%-6% of all ECs, making it the most common form of hereditary EC as well. 7,8 The importance of identifying individuals with LS is further highlighted by the Healthy People 2020 objective, which recommended the following goal: “Increase the proportion of persons with newly diagnosed colorectal cancer who receive genetic testing to identify Lynch syndrome (or familial colorectal cancer syndromes)” (www. healthypeople.gov). Historically, the identification of individuals with possible LS has relied on the family history and pathology-based revised Bethesda guidelines and Amsterdam criteria (Table 2).9-11 However, these criteria are restrictive and have a disproportionate emphasis on CRC, even though the risk of extracolonic cancers may exceed the risk of CRC in LS. More than 1 in 4 cases of LS will be missed even when using the most relaxed criteria, the revised Bethesda guidelines.6 More than half of LS cases do not meet Amsterdam criteria (I or II), resulting in sensitivity as low as 22%.5 Case 1 further highlights the limitations of using age- and family history–based criteria, as the patient did not meet the revised Bethesda guidelines or the Amsterdam criteria I or II. In this circumstance, the universal tumor testing implemented at the hospital where case 1 was treated resulted in the correct diagnosis of LS and the subsequent identification of an early-stage cecal cancer.

Universal tumor testing to screen for LS Given the high rate of missed LS cases when relying on personal and family history criteria, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group evaluated the evidence for and against universal tumor testing of all CRCs.12 After a thorough review of the literature, the EGAPP Working Group concluded that there is sufficient evidence to recommend that all newly diagnosed CRCs should be evaluated for LS.13 EGAPP did not state whether IHC or a second tumor test called microsatellite instability (MSI) should be used.13 There is evidence that IHC and MSI analyses have similar sensitivities for identifying LS.5 IHC, however, is often the preferred tumor-testing method over MSI. IHC has the added benefit of determining which gene(s) might be involved as it assesses specific protein expression. This allows for more targeted genetic testing and therefore may be considered more cost-effective. MSI analysis, on the contrary, evaluates if irregular contractions or expansions of certain microsatellite repeats occur. This phenomenon is called MSI and is an indication of mismatch repair deficiency. Recently, it was shown that histologic grading of CRCs from low to high grade should also include MSI status, as both are related to cancer mortality.14 Mismatch repair deficiency can be owing to either somatic causes (ie, changes that occur after conception) such as hypermethylation of the MLH1 gene promoter or germline causes resulting from an inherited mutation in one of the LS genes. Unlike IHC analysis, MSI does not delineate which gene(s) might be involved. Additional tumor tests, such as BRAF mutation testing and promoter MLH1 hypermethylation testing, are available to help delineate those with sporadic mismatch repair– deficient tumors from those with LS. For further reading on the utility of additional reflex tumortesting protocols, please see Ref. 5. With a formal recommendation from the EGAPP Working Group, universal tumor testing on all recently diagnosed CRCs has been implemented at many hospitals across the United States and internationally.6,15-24 Since the EGAPP recommendation, several other national

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Table 1 Cancer risks, genes associated, and recommendations for management of hereditary CRC syndromes. Syndrome

Gene(s)

Lifetime cancer risks

%*

Screening surveillance

Lynch syndrome

MLH1 MSH2

Colorectum Endometrium

50-80 40-60

MSH6

Stomach

11-19

Colonoscopy every 1-2 y starting at the age of 20-25 y Consider prophylactic hysterectomy and (MLH1, MSH2, and EPCAM) or 30-35 y (MSH6 and PMS2) bilateral salpingo-oophorectomy once childbearing is complete Consider endometrial cancer screening (transvaginal

PMS2 EPCAM

Ovary Hepatobiliary Upper urinary tract Pancreas Small Bowel Glioblastoma

9-12 2-7 4-5 3-4 1-4 1-3

APC

Colorectum

100 (FAP) 70 (AFAP) r1

Stomach Duodenum or periampullary Pancreas Liver (hepatoblastoma) Thyroid Medulloblastoma MAP

n

MUTYH

Colorectum Duodenum

5

ultrasound or endometrial biopsy Consider upper endoscopy every 3-5 y, starting at the age of 30-35 y (MLH1, MSH2, and EPCAM)

Colonoscopy every 1-2 y starting at the age of 10-12 y for Total colectomy when polyp burden too great FAP and late teens for AFAP for endoscopic control Upper endoscopy every 1-3 years starting at the age of 20-25 y

2 1-2

Annual thyroid examination and consider thyroid ultrasound

1-2 o1 80 4

Colonoscopy every 1-2 y, starting at the age of 20-25 y Upper endoscopy every 1-3 y starting at the age of 30-35 y

Total colectomy when polyp burden too great for endoscopic control

Quoted cancer risk ranges are primarily for MLH1, MSH2, and EPCAM mutation carriers; risks for MSH6 and PMS2 mutation carriers are typically lower.

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FAP and AFAP

Preventative surgery

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Table 2 Amsterdam Criteria I and II and revised Bethesda guidelines. Amsterdam Criteria I Requires 3 or more relatives with CRC in addition to the following: (I) One affected individual should be a first-degree relative of the other two (II) Two or more successive generations affected (III) At least one CRC diagnosed at before the age of 50 y (IV) Familial adenomatous polyposis excluded (V) Tumors should be verified by pathologic examination Amsterdam Criteria II Requires 3 or more relatives with HNPCC-associated cancer* in addition to the following: (I) One affected individual should be a first-degree relative of the other two (II) Two or more successive generations affected (III) One or more affected relatives received diagnosis before the age of 50 y (IV) Familial adenomatous polyposis excluded (V) Tumors should be verified by pathologic examination Revised Bethesda guidelines Requires at least one of the following: (I) CRC diagnosed in an individual who is younger than 50 y (II) Presence of synchronous, metachronous CRC, or other HNPCC-associated tumor† (III) CRC diagnosed in an individual who is younger than 60 y with the presence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous or signet-ring differentiation, or medullary growth pattern (IV) CRC diagnosed in an individual with 1 or more first-degree relatives with an HNPCC-associated tumor, with at least 1 of the cancers being diagnosed before the age of 50 y (V) CRC diagnosed in an individual with 2 or more first- or second-degree relatives with HNPCC-associated tumors, regardless of age HNPCC, hereditary nonpolyposis colorectal cancer. n CRC, cancer of the endometrium, small bowel, ureter, or renal pelvis. † Endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas or carcinomas and keratoacanthomas; and carcinoma of the small bowel.

organizations have made consensus statements supporting universal tumor testing of all CRCs, including the National Comprehensive Cancer Network (NCCN), the National Society of Genetic Counselors, the Collaborative Group of the Americas on Inherited Colorectal Cancer, the Association of Molecular Pathology, and the US Multi-Society Task Force on Colorectal Cancer.3,5,25,26 Most consensus statements emphasize universal tumor testing of CRCs. However, current evidence also supports the use of universal tumor testing of all ECs, and many hospitals have successfully implemented this additional screening for LS.8,27-31 Without universal tumor testing, many families with LS will remain undiagnosed. A critical component of universal tumor testing is the involvement of genetic counselors to help develop the appropriate testing protocol; interpret tumor testing results; follow-up on abnormal, and in some cases, normal tumor test results; and coordinate genetic testing in patients and their at-risk relatives once LS is diagnosed.24 The Lynch syndrome Screening Network (LSSN) was specifically formed owing to the complexity of setting up, monitoring, and following through of abnormal tumor test results. The LSSN has created a website (www.lynchscreening.net) that provides access to resources for centers attempting to implement tumor testing at their hospital.24 Resources include information on tumor-testing protocols, example patient fact sheets, supporting guidelines, sample patient letters, information on identifying key stakeholders at institutions, and much more. The LSSN also provides research opportunities for those centers that are performing routine tumor testing at their hospitals.24 Although universal tumor testing is the preferred strategy for evaluating LS, taking a detailed cancer family history is still important, as universal tumor testing focuses on newly diagnosed CRCs and ECs. Therefore, patients with a past personal or family history of cancer meeting revised Bethesda guidelines or Amsterdam criteria or both still need referral to genetic counseling and possibly additional testing. In addition, NCCN has recently endorsed less stringent criteria for LS evaluation in patients with EC diagnosed before the age of 50 years or

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those with a 5% or greater probability of having LS on any of the probability models (PREMM1, 2, 6, MMRpredict, and MMRpro) used to evaluate LS.3 Another key point of case 1 is that BRCA1 and BRCA2 mutations are not the only cause of hereditary ovarian cancer. This was highlighted when the patient’s sister with ovarian cancer was later confirmed to have LS, after previously testing negative for a BRCA1 or BRCA2 mutation. Failure to identify a BRCA1 or BRCA2 mutation in ovarian cancer cases should prompt clinicians to pay attention to other LS cancers in the individual and family to determine if additional testing or referral for genetic counseling or both may be warranted. Medical management Medical management recommendations for LS are outlined in Table 1. Case 1’s CRC was diagnosed even though she showed a normal screening colonoscopy finding 4 years before. LS is documented to have an accelerated adenoma to carcinoma sequence, and hence individuals with LS are recommended to be screened with colonoscopy every 1-2 years. Such a regimen of frequent colonoscopies has been demonstrated to reduce both incidence of CRC as well as CRCrelated mortality among individuals with LS.32,33 Given the variability in CRC risk and age of onset, MLH1, MSH2, and EPCAM mutation carriers are recommended to start colonoscopies at the ages of 20-25 years, whereas individuals with MSH6 or PMS2 mutations are recommended to start later between the ages of 30 and 35 years.3,5 Additional screening and risk-reducing recommendations should be discussed with patients with LS, including consideration of risk-reducing hysterectomy and bilateral salpingooophorectomy. Evidence also supports that the risk of other LS tumors beyond CRC and EC may be lower in MSH6 and PMS2 mutation carriers, therefore additional screening for these tumors is not recommended by NCCN in individuals with mutations in either of these 2 genes.3 Familial implications The cost-effectiveness of LS testing is highly dependent on cascade testing in relatives.34 Cascade testing is defined as the testing of relatives for a known mutation previously identified in their family. Cascade testing is substantially less costly than the initial genetics workup in a proband. Site-specific mutation testing can differentiate with almost 100% certainty who in the family has LS and therefore is at increased risk of LS-associated cancers from those who do not have the familial mutation and are therefore likely to be at average cancer risk. As shown in Figure 1, the patient’s daughter was subsequently found to have the familial MSH6 mutation and therefore was recommended to start colonoscopy immediately. Her son did not have the known familial MSH6 mutation and therefore is expected to be at average risk for CRC. He therefore should follow general population colon cancer screening guidelines and start colonoscopy at the age of 50 years and repeat every 10 years if no polyps are found, barring any other risk factors. As expected (given ovarian cancer is a known LS cancer), the patient’s sister was found to have the familial MSH6 mutation and therefore has LS. The patient’s other sister and brother had negative results and therefore can be spared the increased screening recommended for relatives found to have LS. Cascade testing not only can determine who in the family is in need of increased screening and risk-reducing options, it can also spare family members from unnecessary procedures when they test negative for the known familial mutation. Unfortunately, studies have shown that the uptake of site-specific testing in at-risk relatives is much lower than expected, and further research is needed to optimize this type of testing in these high-risk families.35 Key points

 

LS is the most common form of hereditary CRC and EC, accounting for 2%-6% of all cases. A cost-effective strategy to identify LS is to perform universal tumor testing of all newly diagnosed CRCs and ECs.

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Personal and family history–based criteria, as outlined by the NCCN guidelines, should also be used to identify individuals appropriate for referral for genetic counseling and possible testing. Increased screening and prevention recommendations for LS-associated tumors have been shown to reduce cancer incidence and mortality rates.

Case 2 A 32-year-old male with a 1-month history of hematochezia undergoes his first colonoscopy and is found to have hundreds of polyps from 2-10 mm in size spread throughout the colon and rectum. Biopsies on more than 10 polyps revealed all were tubular adenomas without evidence of high-grade dysplasia or invasive carcinoma. Proctocolectomy with ileal pouch-anal anastomosis was performed. Histopathology revealed hundreds of adenomas throughout the colorectum, in addition to a sigmoid colon cancer. The patient was subsequently referred for genetic counseling. Cancer risk assessment and testing Given the patient’s history of hundreds of colorectal adenomas, he met NCCN guidelines for referral to genetic counseling and genetic testing. During his appointment, he denied any family history of cancer or colon polyps (Fig 2). Even though he meets clinical diagnostic criteria for FAP, which is known to result from APC mutations, it was recommended he have genetic testing of both the APC and MUTYH genes. A germline mutation in the APC was identified, molecularly confirming the diagnosis of FAP. Upper endoscopy was therefore recommended, as per NCCN guidelines, which revealed hundreds of small gastric fundic gland polyps and a 5-mm adenoma in the duodenum. Genetic testing in his 3 children revealed that his 10-year-old daughter and 12-year-old son were both positive for the familial APC mutation, whereas his 8-year-old daughter was negative for it. The patient is believed to have a de novo (new) mutation, as both of his parents were subsequently found not to carry the familial APC mutation. Familial adenomatous polyposis FAP is an autosomal dominant condition caused by mutations in the APC gene. Approximately 25% of cases are the result of a de novo mutation and therefore have no family history of the disease in previous generations.36,37 FAP is characterized by hundreds to thousands of adenomatous polyps of the colorectum. In untreated individuals, the risk of CRC in FAP is inevitable and approaches 100%. The average age of CRC onset is 39 years without intervention. A clinical diagnosis of FAP is often considered when more than 100 colonic adenomas are found. However, genetic testing is imperative in these cases to differentiate FAP from other colonic polyposis conditions. In addition, confirmation of an APC mutation in these cases allows for atrisk relatives to undergo cascade testing. Gastric polyps are found in most individuals with FAP, and duodenal polyps are found in 20%90% of cases.38 Gastric fundic gland polyps may number in the hundreds to thousands. Gastric adenomas may also occur in FAP, though rare, and the risk of gastric cancer is often quoted as 1% or less in FAP kindreds.39 Duodenal polyps in FAP are adenomas, and the lifetime risk of duodenal cancer is approximately 5%.38 Other characteristic features of FAP include desmoid tumors in approximately 10%-30% of patients, most commonly intra-abdominal in location.40 Although lacking metastatic potential, desmoid tumors are the second leading cause of mortality in FAP and are often difficult to treat. Other characteristics of FAP include osteomas, epidermoid cysts, fibromas, dental abnormalities, and congenital hypertrophy of the retinal pigment epithelium. Individuals with these

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Fig. 2. Personal and family history of cancer or polyps in addition to genetic test results for case 2 with familial adenomatous polyposis (FAP).

nonmalignant features and colonic polyposis were originally described as having Gardner syndrome.41 This is now considered a historical term since the determination that Gardner syndrome is also the result of an APC mutation. FAP also confers an increased risk for thyroid cancer and hepatoblastomas in the pediatric population.42,43

Attenuated FAP A milder form of FAP exists, called attenuated FAP (AFAP). AFAP is also caused by germline APC mutations, though the location and type of mutations in APC can assist in determining if individuals have FAP or AFAP (genotype-phenotype correlation). On average, individuals with AFAP develop approximately 30 colonic adenomatous polyps, with an average age of CRC onset in the 50s.44,45 The gastric and duodenal phenotype in FAP is similar to that found in AFAP, thus upper gastrointestinal screening recommendations are the same for both. Other extracolonic features including desmoids, osteomas, epidermoid cysts, and congenital hypertrophy of the retinal pigment epithelium are uncommon in AFAP.44

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Medical management and familial implications Medical management recommendations for FAP and AFAP are outlined in Table 2. The high lifetime risk of CRC in FAP and AFAP warrants earlier and more frequent colonoscopies. Individuals with FAP should start colonoscopic screening around the age of 10-12 years, whereas individuals with AFAP are recommended to start in the late teenage years, typically around 18 years of age.3 Genetic testing of minors is warranted for individuals at risk for FAP, given that colonoscopies are recommended by the age of 10-12 years. For individuals at risk for AFAP, genetic testing can be delayed until the late teenage years. Additional screening is recommended for both FAP and AFAP, including esophagogastroduodenoscopy (EGD) with side-viewing scopes and thyroid examinations. EGDs are important given duodenal cancer is the second most common cancer in FAP and AFAP. Because case 2’s son and daughter with the APC mutation are both at least 10 years of age, colonoscopy was recommended to start immediately. Although sigmoidoscopies are sometimes used initially in FAP, colonoscopies should be used in AFAP as patients’ polyps tend to have rightsided colon predominance and will often be missed by sigmoidoscopies. To prevent CRC, colectomies will be necessary in the future for the patient’s 2 children with FAP, though this can often be delayed until the 20s. His 8-year-old daughter who was negative for the familial APC mutation (a true negative) can start colon cancer screening at the routine age of 50 years. Key points

   

FAP is characterized by hundreds to thousands of colonic adenomas, whereas AFAP on average has only 30 colon polyps. FAP is the result of a de novo APC mutation in approximately 25% of cases and therefore affected individuals in previous generations will be lacking. Desmoid tumors are the second leading cause of mortality in FAP. Genetic testing is imperative in patients with multiple adenomas to differentiate FAP and AFAP from other colonic polyposis conditions.

Case 3 A 50-year-old healthy man undergoes his first screening colonoscopy. He is found to have “many” polyps spread throughout the colon. The specific number, size, or location of polyps is not reported. Biopsies of 2 polyps were obtained, and histopathology revealed a sessile serrated polyp and a tubular adenoma. Patient was subsequently referred for genetic counseling owing to his polyp history. Cancer risk assessment and genetic testing Given the limited information on the number and types of colon polyps, the patient was referred for a repeat colonoscopy where the gastroenterologist appropriately documented the specific number (35-40) and location (cecum to the descending colon) of polyps. In addition, biopsies of more than 20 polyps were obtained, and histopathology revealed all were tubular adenomas. His rectum was spared of polyps. Given the number of adenomas and his young age of polyp onset, testing of the APC and MUTYH genes was performed. The patient was found to have biallelic MUTYH mutations (G396D and Y179C). The patient comes from a large family, and all relatives are reportedly free of cancer or colon polyps (Fig 3). MUTYH-associated polyposis Unlike LS and FAP, MAP is inherited in an autosomal recessive pattern. MAP is the result of biallelic (homozygous or compound heterozygous) mutations in the MUTYH gene, which is part

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Fig. 3. Personal and family history of cancer or polyps and genetic test results for case 3 with MUTYH-associated polyposis (MAP).

of the base excision repair pathway. Compared with FAP, which was first described in the literature possibly as early as 1861, MAP was not described until 2002 when 3 siblings were found to have colorectal polyps or cancer or both.46,47 The colonic phenotype of MAP can mimic both classic FAP and AFAP.48 Individuals with MAP typically have between 10 and 100 polyps, though individuals with up to 500 polyps have been reported.49 The lifetime risk of CRC in untreated individuals approaches 80%.48,50 MAP can also mimic LS with young-onset CRC and few to no polyps, which has also been seen in AFAP.44,51 Individuals with one MUTYH mutation, as is the case for a number of the family members of case 3, are not believed to be at high risk for CRC, and conflicting evidence questions whether there is any increased risk of CRC for these monoallelic mutation carriers.48 In addition to colonic adenomatous polyposis, MAP is also associated with multiple sessile serrated polyps and hyperplastic polyps.52 Neither of these polyp types is known to be associated with AFAP or FAP. Some individuals with MAP have even been found to have enough sessile serrated polyps or hyperplastic polyps or both that they meet diagnostic criteria for serrated polyposis, a condition with no known genetic etiology to date.52-54 A key component of a comprehensive cancer risk assessment for patients with colonic polyposis is to document the type, number, size, and location of the polyps. This information was not provided for case 3, resulting in a delayed diagnosis and a repeat colonoscopy for the patient. Only 2 colon polyps were originally removed, resulting in only 1 documented adenoma. NCCN guidelines state that 10 adenomas are required to meet testing criteria for APC and MUTYH.3 It was not until his second colonoscopy that he was confirmed to meet NCCN guidelines for genetic testing. A detailed description of the location and number of polyps is also critical for determining whether colectomy is needed and the extent of surgery required. MAP is not known to be associated with gastric fundic gland polyposis, as is the case for FAP and AFAP. The risk for duodenal cancer is similar among these syndromes, with MAP having a 4%

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lifetime risk of duodenal cancer (Table 1).55 Other malignancies have been reported in MAP, though the data are not clear if there is truly a significantly increased risk for these cancers.55-57 Medical management and familial implications Similar to AFAP, individuals with MAP need earlier and more frequent colonoscopies, typically starting around the age of 20-25 years and repeating every 1-2 years. They also are recommended to undergo EGDs given the increased risk of duodenal cancer.33 Because MAP is inherited in an autosomal recessive pattern, multiple affected generations rarely occur in MAP families. Siblings of MAP cases have a 25% chance of having MAP and should be offered sitespecific testing for the mutation(s) found in the family. Family members found to have no MUTYH mutations, or only 1, are generally recommended to follow population-based screening recommendations. Children and parents of MAP cases are obligate carriers of one MUTYH mutation. Given the relative frequency of MUTYH mutation carriers in the general population (1 in 100 people), the unaffected parent should undergo full MUTYH genetic testing to exclude the possibility of MAP in their children. If this parent does carry a MUTYH mutation, their children would have a 1 in 2 (50%) chance of having MAP. The spouse of case 3 showed negative finding for a MUTYH mutation (Fig 3), therefore their children are not at risk for this condition. Performing MUTYH testing in the spouse thus spared 5 individuals from needing genetic testing and increased colonoscopy surveillance. Given the lack of evidence supporting a high risk of CRC associated with MUTYH carriers, general population CRC screening was recommended for the children of case 3. Key points

  

Unlike LS, FAP, and AFAP, MAP is inherited in an autosomal recessive pattern. The colonic phenotype in MAP is quite variable, with few or no polyps to hundreds of colon adenomas. MAP can therefore mimic both FAP and AFAP but can also have multiple sessile serrated and hyperplastic polyps. Genetic confirmation of MAP is especially helpful for clarifying risk to relatives.

Summary LS, FAP, AFAP, and MAP are the most common forms of hereditary CRC, and LS is also the most common cause of hereditary EC. Various consensus guidelines have been developed to identify patients with LS. However, recent evidence suggests that screening all newly diagnosed CRCs and ECs for LS syndrome is a cost-effective strategy to identify LS cases and their at-risk relatives. Various testing protocols have been used for universal tumor screening, and the involvement of genetics professionals is a key component to the success of many of these programs. The LSSN has developed and published online (www.lynchscreening.net) various resources that can assist hospitals trying to start a universal or routine tumor-testing program. Regardless if universal tumor testing is being performed or not, a detailed personal and family history is still a critical component of patient care and individuals with young-onset cancers, multiple colon polyps, rare tumors, or multiple related cancers (in the patients or family members or both) should be referred for genetic counseling as outlined and updated annually in various NCCN guidelines. Oncologists and other health care providers can play a key role in the precise diagnosis of hereditary CRC syndromes by identifying patients appropriate for genetic counseling referral. Identifying patients at risk for various hereditary syndromes has been shown to result in prevention and early detection of cancers in these high-risk families, thus saving lives.

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