Sapna Syngal

American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility

The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and management of individuals with an inherited susceptibility to cancer are core elements of oncology care. ASCO released its first statement on genetic testing in 1996 and updated that statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact of advances in this area on oncology practice. In particular, there was an interest in addressing the opportunities and challenges arising from the application of massively parallel sequencing-also known as next-generation sequencing-to cancer susceptibility testing. This technology introduces a new level of complexity into the practice of cancer risk assessment and management, requiring renewed effort on the part of ASCO to ensure that those providing care to patients with cancer receive the necessary education to use this new technology in the most effective, beneficial manner. The purpose of this statement is to explore the challenges of new and emerging technologies in cancer genetics and provide recommendations to ensure their optimal deployment in oncology practice. Specifically, the statement makes recommendations in the following areas: germline implications of somatic mutation profiling, multigene panel testing for cancer susceptibility, quality assurance in genetic testing, education of oncology professionals, and access to cancer genetic services.

ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient’s informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz–Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.

Frequent Detection of Pancreatic Lesions in Asymptomatic High-Risk Individuals

BACKGROUND & AIMS The risk of pancreatic cancer is increased in patients with a strong family history of pancreatic cancer or a predisposing germline mutation. Screening can detect curable, noninvasive pancreatic neoplasms, but the optimal imaging approach is not known. We determined the baseline prevalence and characteristics of pancreatic abnormalities using 3 imaging tests to screen asymptomatic, high-risk individuals (HRIs). METHODS We screened 225 asymptomatic adult HRIs at 5 academic US medical centers once, using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS). We compared results in a blinded, independent fashion. RESULTS Ninety-two of 216 HRIs (42%) were found to have at least 1 pancreatic mass (84 cystic, 3 solid) or a dilated pancreatic duct (n = 5) by any of the imaging modalities. Fifty-one of the 84 HRIs with a cyst (60.7%) had multiple lesions, typically small (mean, 0.55 cm; range, 2-39 mm), in multiple locations. The prevalence of pancreatic lesions increased with age; they were detected in 14% of subjects younger than 50 years old, 34% of subjects 50-59 years old, and 53% of subjects 60-69 years old (P < .0001). CT, MRI, and EUS detected a pancreatic abnormality in 11%, 33.3%, and 42.6% of the HRIs, respectively. Among these abnormalities, proven or suspected neoplasms were identified in 85 HRIs (82 intraductal papillary mucinous neoplasms and 3 pancreatic endocrine tumors). Three of 5 HRIs who underwent pancreatic resection had high-grade dysplasia in less than 3 cm intraductal papillary mucinous neoplasms and in multiple intraepithelial neoplasias. CONCLUSIONS Screening of asymptomatic HRIs frequently detects small pancreatic cysts, including curable, noninvasive high-grade neoplasms. EUS and MRI detect pancreatic lesions better than CT.

Calculation of Risk of Colorectal and Endometrial Cancer Among Patients With Lynch Syndrome

BACKGROUND & AIMS Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome. Some previous estimates of lifetime risk for CRC and endometrial cancer (EC) did not control for ascertainment and were susceptible to bias toward overestimated risk. METHODS We studied 147 families with mismatch repair gene mutations (55 MLH1, 81 MSH2, and 11 MSH6) identified at 2 US cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance. RESULTS We analyzed 628 cases of CRC, diagnosed at the median ages of 42 and 47 years for men and women, respectively. The cumulative risk of CRC was 66.08% (95% confidence interval [CI], 59.47%-76.17%) for men and 42.71% (95% CI, 36.57%-52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1. There were 155 cases of EC, diagnosed at a median age of 47.5 years. The cumulative risk of EC was 39.39% (95% CI, 30.78%-46.94%) with an overall HR of 39.0 (95% CI, 30.4-50.2). For women, the cumulative risk of CRC or EC was 73.42% (95% CI, 63.76%-80.54%). CONCLUSIONS Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary.

Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1

BACKGROUND AND AIMS There are multiple criteria for the clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC). The value of several of the newer proposed diagnostic criteria in identifying subjects with mutations in HNPCC associated mismatch repair genes has not been evaluated, and the performance of the different criteria have not been formally compared with one another. METHODS We classified 70 families with suspected hereditary colorectal cancer (excluding familial adenomatous polyposis) by several existing clinical criteria for HNPCC, including the Amsterdam criteria, the Modified Amsterdam criteria, the Amsterdam II criteria, and the Bethesda criteria. The results of analysis of the mismatch repair genes MSH2and MLH1 by full gene sequencing were available for a proband with colorectal neoplasia in each family. The sensitivity and specificity of each of the clinical criteria for the presence of MSH2 andMLH1 mutations were calculated. RESULTS Of the 70 families, 28 families fulfilled the Amsterdam criteria, 39 fulfilled the Modified Amsterdam Criteria, 34 fulfilled the Amsterdam II criteria, and 56 fulfilled at least one of the seven Bethesda Guidelines for the identification of HNPCC patients. The sensitivity and specificity of the Amsterdam criteria were 61% (95% CI 43-79) and 67% (95% CI 50-85). The sensitivity of the Modified Amsterdam and Amsterdam II criteria were 72% (95% CI 58-86) and 78% (95% CI 64-92), respectively. Overall, the most sensitive criteria for identifying families with pathogenic mutations were the Bethesda criteria, with a sensitivity of 94% (95% CI 88-100); the specificity of these criteria was 25% (95% CI 14-36). Use of the first three criteria of the Bethesda guidelines only was associated with a sensitivity of 94% and a specificity of 49% (95% CI 34-64). CONCLUSIONS The Amsterdam criteria for HNPCC are neither sufficiently sensitive nor specific for use as a sole criterion for determining which families should undergo testing for MSH2 and MLH1mutations. The Modified Amsterdam and the Amsterdam II criteria increase sensitivity, but still miss many families with mutations. The most sensitive clinical criteria for identifying subjects with pathogenic MSH2 andMLH1 mutations were the Bethesda Guidelines; a streamlined version of the Bethesda Guidelines may be more specific and easier to use in clinical practice.

Risk of pancreatic cancer in families with Lynch syndrome

CONTEXT Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified. OBJECTIVE To estimate pancreatic cancer risk in families with germline MMR gene mutations. DESIGN, SETTING, AND PATIENTS Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n = 80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n = 67), Ann Arbor, Michigan. Families enrolled before the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment. MAIN OUTCOME MEASURES Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk. RESULTS Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% (95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase (95% CI, 4.7-15.7) compared with the general population. CONCLUSIONS Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.

ATM Mutations in Patients with Hereditary Pancreatic Cancer

UNLABELLED Pancreatic cancers are the fourth most-common cause of cancer-related deaths in the Western world, with >200,000 cases reported in 2010. Although up to 10% of these cases occur in familial patterns, the hereditary basis for predisposition in the vast majority of affected families is unknown. We used next-generation sequencing, including whole-genome and whole-exome analyses, and identified heterozygous, constitutional, ataxia telangiectasia mutated (ATM) gene mutations in 2 kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wild-type allele. By using sequence analysis of an additional 166 familial pancreatic cancer probands, we identified 4 additional patients with deleterious mutations in the ATM gene, whereas we identified no deleterious mutations in 190 spouse controls (P = 0.046). When we considered only the mostly severely affected families with 3 or more pancreatic cancer cases, 4 deleterious mutations were found in 87 families (P = 0.009). Our results indicate that inherited ATM mutations play an important role in familial pancreatic cancer predisposition. SIGNIFICANCE The genes responsible for the majority of cases of familial pancreatic ductal adenocarcinoma are unknown. We here identify ATM as a predisposition gene for pancreatic ductal adenocarcinoma. Our results have important implications for the management of patients in affected families and illustrate the power of genome-wide sequencing to identify the basis of familial cancer syndromes.

Gynecologic cancer as a sentinel cancer for women with hereditary nonpolyposis colorectal cancer syndrome

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40–60% lifetime risk for colon cancer, a 40–60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their “sentinel cancer.” METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the “sentinel cancer,” preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome. LEVEL OF EVIDENCE: II-3

Obesity Increases the Risks of Diverticulitis and Diverticular Bleeding

BACKGROUND & AIMS Studies of obesity and diverticular complications are limited. We assessed the relationship between body mass index (BMI), waist circumference, and waist-to-hip ratio and diverticulitis and diverticular bleeding. METHODS A prospective cohort study of 47,228 male health professionals (40-75 years old) who were free of diverticular disease in 1986 (baseline) was performed. Men reporting newly diagnosed diverticular disease on biennial follow-up questionnaires were sent supplemental questionnaires. Weight was recorded every 2 years, and data on waist and hip circumferences were collected in 1987. RESULTS We documented 801 incident cases of diverticulitis and 383 incident cases of diverticular bleeding during 18 years of follow-up. After adjustment for other risk factors, men with a BMI >or= 30 kg/m(2) had a relative risk (RR) of 1.78 (95% confidence interval [CI], 1.08-2.94) for diverticulitis and 3.19 (95% CI, 1.45-7.00) for diverticular bleeding compared with men with a BMI of <21 kg/m(2). Men in the highest quintile of waist circumference, compared with those in the lowest, had a multivariable RR of 1.56 (95% CI, 1.18-2.07) for diverticulitis and 1.96 (95% CI, 1.30-2.97) for diverticular bleeding. Waist-to-hip ratio was also associated with the risk of diverticular complications when the highest and lowest quintiles were compared, with a multivariable RR of 1.62 (95% CI, 1.23-2.14) for diverticulitis and 1.91 (95% CI, 1.26-2.90) for diverticular bleeding. Adjustment for BMI did not change the associations seen for waist-to-hip ratio. CONCLUSIONS In this large prospective cohort, BMI, waist circumference, and waist-to-hip ratio significantly increased the risks of diverticulitis and diverticular bleeding.

Benefits of Colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations

Colorectal cancer is the second leading cause of cancer-related death in the United States [1]. Up to 15% of patients with colorectal cancer have a first-degree relative with the disease [2, 3]. In most cases, risk for colorectal cancer is likely to be a complex interaction of genetic and environmental factors. In a subset of patients, however, increased susceptibility to colorectal cancer is inherited through a single gene mutation. Genetic testing for predisposition to cancer is now possible for many hereditary syndromes, including hereditary breast and ovarian cancer, multiple endocrine neoplasia, von Hippel-Lindau disease, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer, the most common hereditary colon cancer syndrome [4], is a dominantly inherited disease that is estimated to account for approximately 2% to 5% of colorectal cancers [5, 6]. The isolation of several DNA mismatch repair genes (hMSH2, hMLH1, hPM2, and hMSH6) associated with hereditary nonpolyposis colorectal cancer has made it possible to identify carriers of a mutated gene within a family [7-11]. On the basis of literature review and expert opinion, investigators from the National Human Genome Research Institute Cancer Genetics Studies Consortium recently recommended that carriers of a mutation for hereditary nonpolyposis colorectal cancer undergo regular colonoscopic surveillance every 1 to 3 years [12]. However, because of the high risk for cancer and metachronous tumors and the limitations of surveillance, the panel recommended that subtotal colectomy with ileorectal anastomosis be considered in patients with colon cancer or adenomas and total proctocolectomy be considered in those with rectal cancer [12]. A definitive answer to the optimal management approach for carriers of a mutation will require clinical studies of large numbers of patients followed prospectively over a long time. However, with the increasing use of genetic predisposition testing, patients and health care providers must decide on cancer risk-reduction strategies now. This decision involves weighing several factors, including the high risk for cancer; surgical and procedure-associated risks; and the health-related quality of life associated with prophylactic colectomy, endoscopic surveillance, and having cancer. We used a decision analysis to assess the outcomes of various colorectal cancer preventive strategies, including colonoscopic surveillance, prophylactic colectomy, and delayed colectomy for patients carrying a genetic mutation associated with hereditary nonpolyposis colorectal cancer. Methods Model Structure We constructed a Markov model by using the decision analysis program DATA (TreeAge Software, Inc., Williamstown, Massachusetts) to compare different approaches to colorectal cancer prevention in patients with a mutation for hereditary nonpolyposis colorectal cancer. The model follows a hypothetical cohort of patients over time and tracks the annual incidence of polyps and colorectal cancer (by stage), progression of colorectal cancer, and mortality (Figure 1). Short-term mortality associated with surgery and endoscopic surveillance was also incorporated. Figure 1. General model framework. Standard therapy for average-risk patients with colorectal cancer is segmental resection of the involved colon and appropriate stage-specific therapy for advanced disease. More aggressive prophylactic colonic resection as a cancer prevention method is the only management option for patients with familial adenomatous polyposis, another group at high risk for colorectal cancer. We evaluated two types of colectomy for carriers of a mutation for hereditary nonpolyposis colorectal cancer: proctocolectomy with ileoanal anastomosis, which was assumed to eliminate all risk for colorectal cancer and the need for postoperative surveillance, and subtotal colectomy with ileorectal anastomosis, which required continued surveillance of the remaining rectal segment. It has been recommended that at-risk patients from families with hereditary nonpolyposis colorectal cancer begin surveillance at 25 years of age or when they are 5 years younger than the youngest age at which cancer was diagnosed in a family member [5]. Because our analysis deals with mutation carriers, we adopted the more aggressive surveillance approach and assumed that surveillance began at 25 years of age. Surveillance was defined as colonoscopy every 3 years if no surgical intervention had been performed [13] and flexible sigmoidoscopy of the remaining rectal segment every 3 years after subtotal colectomy. Surveillance was assumed to stop at 85 years of age. All colorectal cancer was assumed to arise from colorectal adenomas [14-18], and adenomas detected by surveillance were assumed to be removed at the time of colonoscopy. The incidence of adenomas was assumed to be the same as that of cancer except that adenomas could be detected by colonoscopy 5 years before cancer was detected [19]. We examined the following 12 strategies for a cohort of 25-year-old patients who are cancer-free and have a known mutation for hereditary nonpolyposis colorectal cancer: immediate prophylactic proctocolectomy, immediate prophylactic subtotal colectomy, surveillance until 40 years of age followed by prophylactic proctocolectomy, surveillance until 40 years of age followed by subtotal colectomy, surveillance until 50 years of age followed by prophylactic proctocolectomy, surveillance until 50 years of age followed by subtotal colectomy, surveillance and proctocolectomy if an adenomatous polyp is found, surveillance and subtotal colectomy if an adenomatous polyp is found, surveillance and proctocolectomy if invasive cancer is diagnosed, surveillance and subtotal colectomy if invasive cancer is diagnosed, surveillance and segmental resection if invasive cancer is diagnosed, and no surveillance and segmental resection if invasive cancer is diagnosed. Figure 2 shows schematic representations of 2 of these strategies. Model outcomes were life expectancy and quality-adjusted life expectancy. Figure 2. Schematic representation of surveillance and colectomy if adenoma is found. Top. Bottom. Data Sources and Assumptions The probabilities and sources used in the model are listed in Table 1. The risk for colorectal cancer in mutation carriers was based on observed risks of colorectal cancer in a study of 210 carriers of an hMSH2 or hMLH1 mutation [20]. Mean risks for colorectal cancer among men and women in this study and in our baseline analysis were 31.5% by 40 years of age, 54.5% by 50 years of age, 63.0% by 60 years of age, and 87.5% by 75 years of age [20]. Age-specific incidence rates beyond 75 years of age were based on data from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program [21], resulting in a lifetime risk for colorectal cancer of 88.2%. The lifetime risk for a second primary colorectal cancer was 45% [38]. Colorectal cancers in patients with hereditary nonpolyposis colorectal cancer who do not undergo regular surveillance were assumed to follow the same stage distribution as population rates, obtained from the SEER Program: 39% for localized cancer, 40% for regional cancer, and 21% for distant cancer [21]. Table 1. Input Variables Used in Baseline Analyses and Ranges of Sensitivity Analyses Performed Because no long-term follow-up studies of patients with hereditary nonpolyposis colorectal cancer undergoing colectomy have been published, we relied on studies of patients with familial adenomatous polyposis. Long-term follow-up of patients with familial adenomatous polyposis who have undergone proctocolectomy has shown that colorectal cancer in persons who were cancer-free at the time of surgery is rare [39-41]. In theory, prophylactic proctocolectomy eradicates all large-bowel mucosa at risk for colorectal cancer [42]. A prophylactic proctocolectomy was thus assumed to be 100% protective against colorectal cancer in the baseline analysis. The risk for colorectal cancer after subtotal colectomy with ileorectal anastomosis in patients with familial adenomatous polyposis ranges from 3.6% to 32% [22-25]. On the basis of these studies, prophylactic subtotal colectomy was assumed to result in an 80% reduction in lifetime risk for colorectal cancer in carriers of a mutation for hereditary nonpolyposis colorectal cancer (resulting in a lifetime risk for colorectal cancer of 17.5%). The stage-specific mortality rate associated with colorectal cancer was equal to that associated with resection alone or colectomy at the time of cancer diagnosis [39]; however, the risk for a second primary colorectal cancer was reduced by 80% with subtotal colectomy and by 100% with proctocolectomy. We assumed a perioperative mortality rate of 0.4% to 5.6% (depending on age) for persons undergoing prophylactic colectomy [26-28] and 0.8% to 11.2% (depending on age) for surgical resection of colorectal cancer [28, 29]. The largest prospective, controlled study of hereditary nonpolyposis colorectal cancer found that surveillance resulted in a 62% decrease in risk for colorectal cancer [30]. On the basis of this information, we used a constant percentage reduction each year so that the predicted lifetime risk was reduced by 62%. All colorectal cancer was assumed to be diagnosed at a localized stage (Dukes stage A or B1), as was the case in the largest trial of colonoscopic surveillance in the general population (the National Polyp Study [13, 31]) and in patients with hereditary nonpolyposis colorectal cancer who undergo surveillance [30, 33]. The mortality rate associated with endoscopic surveillance was 0.02%, based on several large studies of complications associated with endoscopic procedures [34-37]. Age- and sex-specific mortality estimates were obtained from U.S. life tables [43]. In our baseline analysis, we assumed that stage-specific colorectal canc