Hereditary Colorectal Cancer Syndrome Research Articles

Update on small bowel surveillance in hereditary colorectal cancer syndromes.

Despite its rarity in the general population, small bowel adenocarcinoma risk is increased in individuals with hereditary colorectal cancer syndromes (HCCS). In the last decade, the advent of capsule endoscopy and device-assisted balloon enteroscopy procedures in patients with HCCS have allowed to investigate the whole small bowel, increasing the diagnostic yield of small bowel tumor. Nonetheless, there is a significant variability in the international guideline recommendations. The aim of this review is to provide an update on surveillance of small bowel in HCCS and to identify the key points for the clinical management of these patients.

Management of rectal neoplasia in hereditary colorectal cancer patients

Determining the optimal treatment for rectal cancer is a complicated challenge on its own but requires even more careful consideration when it occurs in patients with a hereditary colorectal cancer syndrome. Ideally, these patients are identified early and followed closely to prevent cancer. If cancer does arise, the standardized strategy for rectal cancer treatment used for the general population must be tailored to address the concerns of risk for metachronous neoplasia and functional outcomes that are unique to these patients. The best surgical approach considers both the primary cancer as well as the remaining unstable colorectum, and thoughtful timing of multimodal therapies helps to avoid negative effects on bowel reconstruction to maintain quality of life.

Value of EGD for gastric cancer surveillance in patients with hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome (LS).

1522Background: Gastric cancer (GC) is the second most common non-gynecologic malignancy in patients with LS. Due to an absence of prospective randomized data, the value of esophago-gastro-duodenos...

Identity, community and care in online accounts of hereditary colorectal cancer syndrome

Sociological literature has explored how shifts in the point at which individuals may be designated as diseased impact upon experiences of ill health. Research has shown that experiences of being genetically “at risk” are shaped by and shape familial relations, coping strategies, and new forms of biosociality. Less is known about how living with genetic risk is negotiated in the everyday and over time, and the wider forms of identity, communities and care this involves. This article explores these arrangements drawing on online bloggers’ accounts of Familial Adenomatous Polyposis (FAP). We show how accounts of genetic risk co-exist with more palpable experiences of FAP in everyday life, notably the consequences of prophylactic surgeries. We consider how the act of blogging represents but also constitutes everyday experiences of hereditary cancer syndrome as simultaneously ordinary and exceptional, and reflect on the implications of our analysis for understanding experiences of genetic cancer risk.

Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1,MSH2,MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice‐site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one‐third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome.

MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques

Over the past two decades, 33 cases of colonic adenocarcinomas have been diagnosed in rhesus macaques (Macaca mulatta) at the nonhuman primate colony of the Keeling Center for Comparative Medicine and Research at The University of Texas MD Anderson Cancer Center. The distinctive feature in these cases, based on PET/computed tomography (CT) imaging, was the presence of two or three tumor lesions in different locations, including proximal to the ileocecal juncture, proximal to the hepatic flexure, and/or in the sigmoid colon. These colon carcinoma lesions selectively accumulated [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoroacetate ([18F]FACE) at high levels, reflecting elevated carbohydrate and fatty acid metabolism in these tumors. In contrast, the accumulation of [18F]fluorothymidine ([18F]FLT) was less significant, reflecting slow proliferative activity in these tumors. The diagnoses of colon carcinomas were confirmed by endoscopy. The expression of MLH1, MSH2, and MSH6 proteins and the degree of microsatellite instability (MSI) was assessed in colon carcinomas. The loss of MLH1 protein expression was observed in all tumors and was associated with a deletion mutation in the MLH1 promoter region and/or multiple single-nucleotide polymorphism (SNP) mutations in the MLH1 gene. All tumors exhibited various degrees of MSI. The pedigree analysis of this rhesus macaque population revealed several clusters of affected animals related to each other over several generations, suggesting an autosomal dominant transmission of susceptibility for colon cancer. The newly discovered hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques, termed MLH1-rheMac, may serve as a model for development of novel approaches to diagnosis and therapy of Lynch syndrome in humans.

Polyp burden in Lynch syndrome patients ascertained via multigene panel testing.

596 Background: Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (HNPCC), is a hereditary colorectal cancer syndrome thought to present with few or no polyps. It has been suggested that the majority of LS patients with colon polyps will develop 1-9 cumulative adenomatous polyps in their lifetime, while approximately 10% will develop ≥10. Our aim was to describe polyp burden in a cohort of LS patients who were ascertained via multi-gene cancer panel testing. Methods: We retrospectively reviewed the personal history for all individuals with a pathogenic or likely pathogenic variant (collectively, PV) in MLH1, MSH2 (including 3’ EPCAM deletions), MSH6, or PMS2. Individuals with more than one PV in a LS-associated or other gene were excluded. All polyp data was obtained from provided test requisition forms and/or pathology reports. Results: A total of 131 individuals reported to have colon polyps were molecularly confirmed as having LS. Of these individuals, 55% (72/131) reported a history of colorectal cancer. Overall, polyp burden was reported as follows: 83% (109/131) with 1-10 polyps, 13% (17/131) with 10-19 polyps, and 4% (5/131) with 20-50 polyps. Of the 5 individuals reporting 20-50 polyps, the average was 31.2 polyps (range 21-50). Adenomatous pathology was reported for one or more polyps in 69% (91/131) of individuals. When limited to those with adenomatous polyps, 85% (77/91) reported 1-10 polyps, 11% (10/91) reported 10-19 polyps, and 4% (4/91) reported 20-50 polyps. When breaking down by presence and absence of colorectal cancer, 18% (13/72) and 15% (9/59), respectively, reported a polyp burden ≥10. Overall, 17% (22/131) of all LS patients reported ≥10 polyps. Conclusions: Similar to previously published data, the majority of LS patients with colon polyps report a polyp burden of < 10. However, our data suggest that the proportion of LS patients with a polyp burden of ≥10 may be higher than previously reported (17% vs. 10%) stressing the importance of including the LS-associated genes for these patients. While LS has historically been referred to as a “non-polyposis” syndrome, a subset of patients actually present with an attenuated polyposis-like phenotype.

Hereditary gastrointestinal carcinomas and their precursors: An algorithm for genetic testing.

Recognition of hereditary forms of gastrointestinal cancer is of great importance for patients and their families and pathologists play a crucial role in this. This review recapitulates the clinical, pathological and molecular aspects of Hereditary Diffuse Gastric Cancer and Gastric Adenocarcinoma and Proximal Polyposis of the Stomach, as well as hereditary colorectal cancer syndromes such as Lynch syndrome and gastrointestinal polyposis syndromes (including Familial Adenomatous Polyposis, Peutz-Jeghers syndrome and Juvenile Polyposis syndrome). Histopathological clues to recognize hereditary forms of gastrointestinal cancer and possible ancillary studies that can support an underlying syndrome and guide genetic testing are discussed.

Prevalence and characteristics of hereditary non-polyposis colorectal cancer (HNPCC) syndrome in immigrant Asian colorectal cancer patients

BackgroundThe prevalence of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is 2 to 5% in the Caucasian population. HNPCC is caused by genomic mutations in DNA mismatch repair genes (MMR), namely MLH1, MSH2, MSH6, PMS2, and EPCAM. A non-hereditary, acquired process of hypermethylation of the MLH1 promoter can also lead to silencing of MLH1 protein expression. Diagnosis of HNPCC in patients with colorectal and other related cancers is important in the clinical treatment and surveillance of related cancers. The prevalence and clinical characteristics of HNPCC in Asian colorectal cancer patients has been reported in small studies and unique features have been suggested.MethodsWe retrospectively reviewed the clinical characteristics of Asian patients who were diagnosed of colon cancer between 1/2002 and 6/2015, and performed IHC for four MMR protein expressions on tumor specimens as a screening test for HNPCC, followed by confirmatory tests of genomic sequencing and hypermethylation analysis.ResultsOne hundred forty-three patients were identified. Thirty-one patients were diagnosed younger than 50 years old, while 112 patients were diagnosed older than 50 years old. Six cases of HNPCC were found with a prevalence of 4.19%. The prevalence in the group of patients diagnosed younger than 50 years old is 16.1%, and that in patients diagnosed older than 50 years old is 0.89%. All patients with HNPCC had family histories of colon or gastric cancer. Tumor locations in the HNPCC patients were predominantly in the descending or sigmoid colon (67%). Half of the HNPCC patients had MSH6 mutations. Hypermethylation of the MLH1 gene was only present in 2.80% of the patients.ConclusionThe prevalence of HNPCC is high in patients younger than 50 years old and extremely low in those older than 50 years old. These results may be useful in the future development of guidelines for HNPCC laboratory screening among Asian patients. The pathological and clinical features of HNPCC in this group of Asian immigrant patients are more similar to those reported on Asian patients in their home countries than to Caucasian patients in Western countries, and will warrant further large-scale evaluation.

Abstract IA5: Aspirin for precision chemoprevention of colorectal cancer

Abstract Remarkably consistent experimental and epidemiologic evidence demonstrates that aspirin is associated with a lower risk of colorectal cancer. These studies have been complemented by compelling data from randomized controlled trials (RCTs). Five placebo-controlled RCTs among individuals with a history of colorectal adenoma or cancer showed that aspirin reduced the risk of recurrent adenomas, the precursors of the vast majority of cancers. Data from long-term follow-up of the CAPP2 trial, a RCT of aspirin among individuals with the Lynch hereditary colorectal cancer syndrome and the Women's Health Study, a RCT of aspirin among women for primary prevention of cardiovascular disease and cancer demonstrated that randomized aspirin treatment was associated with a lower risk of colorectal cancer. Finally, secondary analyses of RCTs of aspirin for cardiovascular prevention have shown that aspirin reduces incidence of and mortality from colorectal cancer. As a reflection of the strength of the evidence, the U.S. Preventive Services Task Force (USPSTF) updated its primary prevention guidelines for aspirin in 2016. The USPSTF now recommends low-dose aspirin (81 mg/day) for chronic disease prophylaxis, including colorectal cancer prevention, among U.S. adults between ages 50-59, and possibly ages 60-69, with a greater than 10% ten-year risk of cardiovascular events. The new USPSTF recommendation represents a significant milestone for the field of preventive medicine. With the exception of tamoxifen for women at high-risk for breast cancer, this is the first medication broadly recommended for cancer prevention by the USPSTF. Despite this advance, wider scale efforts to implement aspirin chemoprevention are limited by concerns about risk-benefit profile in view of the established association of aspirin with gastrointestinal bleeding. In concert with broader efforts to tailor prevention strategies, our group has led several studies into the mechanistic basis of aspirin's anti-cancer effect that has led to the development of intratumoral, colonic, germline, and circulating molecular correlates of outcomes. Such biomarkers can be exploited for risk stratification to more effectively target aspirin chemoprevention for those with more favorable risk-benefit profiles. In this presentation, we will review the evidence supporting a role for aspirin in the prevention of colorectal cancer, with a focus on novel methods for molecular risk stratification. Such a precision chemoprevention strategy could play a role in global efforts for chronic disease prevention and control. Citation Format: Andrew T. Chan. Aspirin for precision chemoprevention of colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA5.

When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes?

When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes?

Low yield of gastroscopy in patients with Lynch syndrome

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in mismatch-repair genes. Besides a lifetime risk of colorectal cancer averaging 70%-80%, there is an increased risk of extracolonic tumors including gastric cancer. The utility of screening gastroscopy in Lynch syndrome has long been debated. This study aimed to determine the proportion of abnormal gastroscopies among patients screened, including the incidence of gastric cancer and prevalence of precursor lesions. Charts of patients with mutation-proven Lynch syndrome between January 1, 2004, and December 31, 2014, from the Genetics clinic and Hereditary Gastrointestinal Cancer Clinic of our institution were retrospectively reviewed. A total of 66 Lynch syndrome patients were identified. Thirty-two gastroscopies were performed in 21 (32%) of them. No gastric cancers were found. The prevalence of precursor lesions (Helicobacter pylori gastritis, atrophic gastritis, and gastric intestinal metaplasia) was 19.05%. A family history of gastric cancer was associated with a non-significant increased risk of abnormal gastroscopy, while sex and specific gene involved did not affect the abnormality rate. Gastric screening in asymptomatic individuals with Lynch syndrome is probably best reserved for high-risk individuals, based on the family history and perhaps ethnicity as suggested by several governing bodies. Larger studies are required to achieve the statistical power necessary to address this controversial issue.

Continuing Medical Education Questions: October 2017: Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management.

Continuing Medical Education Questions: October 2017: Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management

Continuing Medical Education: October 2017: Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management

Continuing Medical Education: October 2017: Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management

Clinicopathologic Features of Young Onset Colorectal Cancer Patients: Results From a Large Cohort at a Single Cancer Center

Introduction: Whereas the overall incidence of colorectal cancer (CRC) in the United States (US) is decreasing, its incidence in young adults (<50 years old) is increasing. The cause of this remains unclear, and the characteristics of patients with young onset CRC have not been fully elucidated. The aim of this study is to describe the demographics, clinical and pathologic features of patients with young onset CRC. Methods: We performed a retrospective review of all patients with CRC diagnosed between ages 20 and 49 years evaluated at Memorial Sloan Kettering Cancer Center from January 2004 to April 2015. We excluded those with a history of a hereditary CRC syndrome, inflammatory bowel disease, or prior diagnosis of CRC. Patient demographics, presenting symptoms, smoking history, family history of cancer, medical and surgical history, tumor characteristics, and pathology were obtained from the electronic medical record. Baseline characteristics were compared to those found in a nationally representative cohort of cancer-free individuals age 20 to 49 in the US National Health and Nutrition Examination Survey (NHANES). Results: We identified 3,238 young onset CRC patients. Median age of CRC diagnosis was 44; 52% were male (Table 1). Compared with the NHANES population, patients had a lower body mass index (BMI), a higher rate of hypertension and diabetes, and were more likely to have never smoked (Figure 1). The most common presenting symptoms were rectal bleeding (49%), followed by abdominal pain/bloating (33%) and change in bowel habits (25%) (Figure 2). The majority of patients presented with left sided cancers (69%), at late stage disease (65% at stages 3 or 4) (Table 2), and had no family history of CRC (68%) (Table 1).Figure: Comparison of clinical variables for MSK patient population vs. NHANES cancer-free population <50 years old.Figure: Percentage of patients who presented with a given symptom ABBREVIATIONS: BRBPR (bright red blood per rectum); FOBT+ (Fecal occult blood test positive).Table: Table. Demographic Characteristics of Patients ( N =3,238)Table: Table. Cancer Characteristics of MSK Patients Overall and by Age Decade ( N , 3,238)Conclusion: To date, this is the largest single center study describing the demographics, clinical and pathologic features of young onset CRC. Most patients presented with symptoms of rectal bleeding or abdominal pain, left sided cancers, later stage disease and had no family history of CRC. Compared to a US nationally representative population, these patients had a greater prevalence of hypertension and diabetes. More data are needed to better understand risk factors for young onset CRC, and to help identify high-risk patient populations who may benefit from earlier screening.

Germline mutations in patients with multiple colorectal polyps in China.

Multiple colorectal polyps are relevant in hereditary colorectal cancer (CRC) syndromes, which are thought to be caused by multiple events including germline mutations. This study was aimed to characterize germline mutations in Chinese patients with multiple colorectal polyps. Patients with >10 colorectal polyps at the Department of Gastroenterology of the PLA Army General Hospital were enrolled from January 2014 to December 2015. These patients were divided into the high-risk, moderate-risk, and mild-risk groups. White blood cell samples were collected, and DNA was extracted to sequence a panel of 19 genes previously associated with CRC by next-generation sequencing. A total of 96 patients were enrolled in the study. Pathogenic germline mutations were found in 24 (24/33, 72.73%), nine (9/24, 37.5%), and three patients (3/39, 7.7%) in the high-risk, moderate-risk, and mild-risk groups, respectively. Based on the results given, we suggested a strategy about gene sequencing test for the patients with multiple polyps, and the sensitivity and specificity of the screening strategy were 97% and 57%, respectively. Four of eight patients with MUTYH pathogenic germline mutations had the c.A934-2G monoallelic germline mutation, whereas three of eight patients had the C55T MUTYH germline mutation. Concurrent pathogenic germline mutations in APC and MUTYH were also observed. A genetic screening strategy comprising 19 genes was effective to screen for hereditary CRC syndromes in patients with multiple colorectal polyps. The MUTYH germline mutation hotspots in Chinese patients may be different from those in Caucasian patients.

Evaluation of an online family history tool for identifying hereditary and familial colorectal cancer

Identifying a hereditary colorectal cancer (CRC) syndrome or familial CRC (FCC) in a CRC patient may enable the patient and relatives to enroll in surveillance protocols. As these individuals are insufficiently recognized, we evaluated an online family history tool, consisting of a patient-administered family history questionnaire and an automated genetic referral recommendation, to facilitate the identification of patients with hereditary CRC or FCC. Between 2015 and 2016, all newly diagnosed CRC patients in five Dutch outpatient clinics, were included in a trial with a stepped-wedge design, when first visiting the clinic. Each hospital continued standard procedures for identifying patients at risk (control strategy) and then, after a predetermined period, switched to offering the family history tool to included patients (intervention strategy). After considering the tool-based recommendation, the health care provider could decide on and arrange the referral. Primary outcome was the relative number of CRC patients who received screening or surveillance recommendations for themselves or relatives because of hereditary CRC or FCC, provided by genetic counseling. The intervention effect was evaluated using a logit-linear model. With the tool, 46/489 (9.4%) patients received a screening or surveillance recommendation, compared to 35/292 (12.0%) in the control group. In the intention-to-treat-analysis, accounting for time trends and hospital effects, this difference was not statistically significant (p = 0.58). A family history tool does not necessarily assist in increasing the number of CRC patients and relatives enrolled in screening or surveillance recommendations for hereditary CRC or FCC. Other interventions should be considered.

Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management.

Colorectal cancer (CRC) is the fourth most common cancer amongst men and women. Between 3 and 6% of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and several hamartomatous polyposis conditions. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This narrative review examines the hereditary colorectal cancer and polyposis syndromes, their genetic basis, clinical management, and evidence supporting cancer screening.

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

BackgroundMutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next‐generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility.MethodsTargeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age <50 years) (n = 333); (4) proficient mismatch repair (MMR) in cases diagnosed at ≥50 years (n = 68); and (5) deficient MMR CRCs with no germline mutations in MLH1, MSH2, MSH6, or PMS2 (n = 129). Ninety‐three unaffected controls were also sequenced.ResultsOverall, 29 nonsense, 43 frame‐shift, 13 splice site, six initiator codon variants, one stop codon, 12 exonic deletions, 658 missense, and 17 indels were identified. Missense variants were reviewed by genetic counselors to determine pathogenicity; 13 were pathogenic, 61 were not pathogenic, and 584 were variants of uncertain significance. Overall, we identified 92 cases with pathogenic mutations in APC,MLH1,MSH2,MSH6, or multiple pathogenic MUTYH mutations (7.5%). Four cases with intact MMR protein expression by immunohistochemistry carried pathogenic MMR mutations.ConclusionsResults across case subsets may help prioritize genes for inclusion in clinical gene panel tests and underscore the issue of variants of uncertain significance both in well‐characterized genes and those for which limited experience has accumulated.

Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer (HNPCC).

Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome, is an autosomal dominant cancer syndrome that confers an elevated risk of early-onset colorectal cancer (CRC) and increased lifetime risk for other cancers of the endometrium, stomach, small intestine, hepatobiliary system, kidney, ureter, and ovary. Lynch syndrome accounts for up to 3% of all CRC, making it the most common hereditary colorectal cancer syndrome. Germline mutations in methyl-directed mismatch repair (MMR) genes give rise to microsatellite instability (MSI) in tumor DNA. Lynch syndrome is most frequently caused by pathogrenic variants in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Germline mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with Lynch syndrome. Pathogenic vatiants in MSH6 have been reported in approximately 7-10% of families with Lynch syndrome. Pathogenic variants in PMS2 account for fewer than 5% of mutations in families with Lynch syndrome. This unit presents a comprehensive molecular genetic testing strategy for Lynch syndrome including MSI analysis, next generation sequencing (NGS)-based targeted sequence analysis, PCR-based Sanger sequencing and microarray-based comparative genomic hybridization (array-CGH). © 2017 by John Wiley & Sons, Inc.