Hereditary Colorectal Cancer Syndrome Research Articles

High predictability for identifying Lynch syndrome via microsatellite instability testing or immunohistochemistry in all Lynch-associated tumor types.

Lynch syndrome is an inherited cancer-prone syndrome identified in ~3% of all colorectal cancer (CRC) patients and ~2% of all endometrial cancer (EC) patients (1-3). It is defined by identification of a germline mutation in one of the DNA mismatch repair (MMR) genes ( MSH2, MLH1, MSH6, PMS2, EPCAM ) whose proteins function to maintain replication fidelity of DNA prior to mitosis, and sets it apart from other hereditary non-polyposis colorectal cancer (HNPCC) syndromes such as Familial Colorectal Cancer Type X and Polymerase Proofreading Polyposis syndrome (3).

Current recommendations for surveillance, risk reduction and therapy in Lynch syndrome patients

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.

Patients in Whom to Consider Genetic Evaluation and Testing for Hereditary Colorectal Cancer Syndromes.

Patients in Whom to Consider Genetic Evaluation and Testing for Hereditary Colorectal Cancer Syndromes.

Genomic Analyses of Pre-cancers to Accelerate Cancer Interception in Hereditary Colorectal Cancer Syndromes

Abstract The field of colorectal cancer oncology has witnessed major advances in the last decade for the treatment of late-stage cancers using targeted and immune-based therapies. However, there is yet a critical unmet need to develop novel approaches to improve the colorectal cancer prevention. Hereditary colorectal cancer syndromes, mainly Familial Adenomatous Polyposis and Lynch Syndrome, offer a unique opportunity to develop and test the activity of such interventions in high-risk populations displaying an accelerated carcinogenesis. Advances in genomics and systems biology provide unprecedented opportunities to understand the earliest molecular events present in pre-cancer initiation and enable the development of novel strategies to intercept the growth of pre-cancers and their evolution into invasive cancers. In this talk, the speaker will present genomic efforts leveraging next-generation sequencing approaches coupled with big data analysis and will show the potential of this conceptual framework to accelerate advances in cancer prevention that are applicable to other pre-cancers. In addition, challenges inherent to the analysis of pre-cancers and the implementation of clinical studies in Hereditary Cancer Syndromes will be presented. These genomic approaches are likely to bring transformational changes and advances in cancer interception for patients and families with Hereditary Colorectal Cancer Syndromes.

Tumour budding predicts increased recurrence after curative resection for T2N0 colorectal cancer

Tumour budding is defined as the presence of a cluster of fewer than 5 cells along the invasive margin. It may confer a worse prognosis in colorectal cancer, but its importance in pT2N0 colorectal cancer is unknown. This study aimed to determine the prognostic value of tumour budding in pT2N0 colorectal cancer. This was a retrospective cohort study with prospective assessment of tumour budding by 2 pathologists. We included all patients who underwent elective curative resection for pT2N0 colorectal cancer except those with hereditary colorectal cancer syndromes, inflammatory bowel disease or positive resection margins, those who received neoadjuvant or adjuvant therapy and those who died within 90 days of operation. Patients were classified as having high-grade tumour budding (≥ 10 budding foci per high-power field) or low-grade tumour budding (< 9 budding foci per high-power field). The main outcome measure was locoregional or distant recurrence. Of 85 patients, 36 had high-grade tumour budding and 49 had low-grade tumour budding. The overall recurrence rate was 11% (9/85) and median follow-up was 41.0 months (interquartile range 22.0–68.0). Interrater reliability for tumour budding assessment was excellent (κ = 0.86, 95% confidence interval [CI] 0.76–0.96). There were more recurrences in patients with high-grade tumour budding (7/36, 19.4% v. 2/49, 4.1%; p = 0.020). On multivariate analysis, after we adjusted for confounders, the presence of high-grade tumour budding was independently associated with recurrence (hazard ratio 5.11, 95% CI 1.01–25.9). Tumour budding was independently associated with increased recurrence after pT2N0 colorectal cancer resection. It offers additional prognostic information that may affect treatment strategy.

1133 Bariatric Surgery Is Associated With Post-Operative Constipation

INTRODUCTION: Bariatric surgery has become a common therapeutic approach to obesity. However, bariatric procedures may affect bowel habits due to changes in dietary intake as well as altered anatomy. To date, few studies have evaluated the impact of bariatric surgery on post-operative constipation. The aim of this study is to determine if patients experience a greater rate of constipation after bariatric surgery compared to non-bariatric controls. METHODS: A retrospective chart review at New York Langone Hospital (NYU) was performed on 160 bariatric surgery patients who had surgery in the year 2012 and 160 control patients with BMI &lt; 30 kg/m2 seen in primary care in 2012. Reports of constipation were recorded up until November 2018. Exclusion criteria included those with inflammatory bowel disease or hereditary colorectal cancer syndromes prior to age 50. The primary outcome was diagnosis of post-operative constipation. Secondary outcomes included rates of constipation according to surgical procedure. Presence of constipation was recorded if listed on the problem list or if medications for constipation were prescribed. Logistic regression and chi-squared testing was used to assess differences in groups. RESULTS: Table 1 shows patient characteristics of the study population. The average age of bariatric surgery patients was 64.1 years compared to 69.8 in the control group. Overall, 20% of bariatric patients were diagnosed with constipation compared to 15% of controls (P = 0.239). Constipation rates post-bariatric surgery were 17.9% in lap band, 20.6% in sleeve gastrectomy, and 7.1% in gastric bypass patients (P = 0.256). A logistic regression controlling for age, sex, and Charlson co-morbidity index was performed between controls and post-surgery subjects. This revealed no significant difference in rates of constipation between the two groups (OR 1.158, 95% CI 0.790 – 1.696 P-value = 0.45). There was, however, a significant difference in constipation rates between the bariatric group pre-surgery (13.8%) and post-surgery (17.5%) (P = &lt; 0.001) (Table 2). CONCLUSION: Bariatric surgery patients experience significantly higher rates of constipation after surgery compared to prior to surgery, but similar rates to controls without obesity. Constipation impairs quality of life and is associated with significant health care costs. Further studies investigating the mechanisms underlying this increase in constipation after bariatric surgery and effective measures to treat it are warranted.

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019.

Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.

An Update on Inherited Colon Cancer and Gastrointestinal Polyposis.

It is estimated that 5-10% of colorectal cancers arise due to a known genetic syndrome. Individuals with these cancer syndromes are also at risk of extracolonic cancers. Polyposis and nonpolyposis hereditary syndromes are generally recognized. Inclusion of next-generation sequencing technology, especially multiple-gene panel testing, in routine laboratory practice has made identifying the causes of these diseases significantly easier. To summarize current knowledge of the causes, clinical manifestations, diagnostic criteria, and recommendations for presymptomatic screening of individuals at risk of hereditary gastrointestinal polyposis and colorectal cancer syndromes. We dicuss currently defined syndromes detected by multiple-gene panel next-generation sequencing; these include constitutional mismatch repair deficiency (biallelic MLH1, MSH2, MSH6, PMS2 gene mutations), gastric adenocarcinoma and proximal polyposis of the stomach (APC gene), NTHL1-associated polyposis, polymerase proofreading-associated polyposis (POLD1, POLE genes), juvenile polyposis (SMAD4, BMPR1A genes), and serrated polyposis syndromes. Another aim is to summarize recent knowledge about well-known syndromes, including hereditary nonpolyposis colon cancer (Lynch syndrome), familial adenomatous polyposis, MUTYH-associated polyposis, and Peutz-Jeghers and Cowden/PTEN hamartoma tumor syndromes. Awareness of hereditary polyposis/colon cancer syndromes enables early diagnosis and prevention of cancer in affected individuals and their relatives. Genetic counseling, presymptomatic testing of at-risk individuals, and efficient screening may be beneficial for affected families. Thank to Lenka Foretová, M.D., PhD, (Masaryk Memorial Cancer Institute, Brno) for a critical review of the manuscript and valuable advices. The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 1. 3. 2019 Accepted: 6. 6. 2019.

Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum.

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by heterozygous mutations in the mismatch repair (MMR) genes. Biallelic mutations in these genes lead however, to constitutive mismatch repair deficiency (CMMRD). In this study, we follow the diagnostic journey of a 12-year old patient with CRC, with a clinical phenotype overlapping CMMRD. We perform molecular and functional assays to discard a CMMRD diagnosis then identify by exome sequencing and validation in a cohort of 134 LS patients, a candidate variant in the MLH1 UTR region in homozygosis. We propose that this variant, together with other candidates, could be responsible for age-of-onset modulation. Our data support the idea that low-risk modifier alleles may influence early development of cancer in LS leading to a LS-to-CMMRD phenotypic continuum. Therefore, it is essential that larger efforts are directed to the identification and study of these genetic modifiers, in order to provide optimal cancer prevention strategies to these patients.

Abstract 4162: Prevalence of germline mutations and variants of uncertain significance (VUS) among Hispanics with suspected hereditary colorectal cancer syndromes

Abstract Background: Colorectal cancer (CRC) is one of the leading causes of cancer death in Puerto Rico (PR) and U.S. Approximately 5-10% of all CRC cases are due to hereditary CRC syndromes. Some of the most common hereditary colorectal cancer syndromes include: Familial Adenomatous Polyposis (APC), Lynch Syndrome (MLH1, MSH2, MSH6, PMS2) and MUTYCH (MYH). Germline genetic testing is the gold standard for diagnosing these syndromes. The implications of obtaining a Variant of Uncertain Significance (VUS) in germline genetic testing results remains a clinical challenge especially among minority Hispanic populations. The aim of this project was to determine the prevalence of germline pathogenic mutations and VUS in CRC-risk genes; as well as the phenotype of Hispanic patients with suspected Hereditary CRC syndromes. Methods: Germline genetic testing from patients with suspected hereditary CRC syndromes seen at the UPR Cancer Genetic Clinic during the period of 2015-2018 were evaluated. Sociodemographics, clinical, tumor and genetic testing data were accessed through the subject’s medical record. Descriptive statistics and frequency distribution tables were generated with the subject’s sociodemographic and clinical information, as well as germline genetic testing results. Results: A total of 91 patients (61.5% female; mean age 51 years) with suspected hereditary CRC syndromes were tested for germline mutations in relevant CRC-risk genes. The most common malignancies reported were CRC (80%) and endometrial cancer (12%). The majority of patients (n=60) did not have germline mutations in hereditary CRC-risk genes. Mutations in CRC-risk genes were detected in 22% of patients (50% MYH, 45% MMR, 5% APC), while VUSs were detected in 12% (18% MYH, 45% MMR, 36% APC). There were no statistically significant differences with regards to gender, age, personal history of cancer or 1st degree family history of cancer across study groups. All patients with VUSs in MMR-genes had microsatellite stable tumors; while those with mutations in MMR-genes had microsatellite unstable tumors. Conclusions: VUSs were present in a high-percentage of the patients evaluated for hereditary CRC syndromes. Furthermore, there were no phenotypical differences between patients with pathogenic mutations and those with VUSs. This presents a clinical challenge as non-European populations including Hispanics have genetic variances, which may in fact carry an increase risk for cancer. Future research is warranted to examine the significance and/or reclassify VUSs to improve assessment of genetic test results in admixed populations. Citation Format: Julyann Perez-Mayoral, Nicole Cruz-Reyes, Andrea Rosa-Vazquez, Maria Gonzalez-Pons, Marcia Cruz-Correa. Prevalence of germline mutations and variants of uncertain significance (VUS) among Hispanics with suspected hereditary colorectal cancer syndromes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4162.

Abstract 4161: Germline mutational profileof Chinese patients with colorectal cancer and diagnosed lower than 70 years

Abstract Background/Aims: Colorectal cancer (CRC) is a common cancer worldwide with increasing morbidity in China. Approximately 5% CRC are caused by well-defined hereditary CRC syndromes, whose inherited susceptibility account for nearly one-third of CRC predisposition. Most of hereditary CRC syndromes were diagnosed at the age of lower than 70, whereas little is known about the mutational profiles Chinese patients and their correlations with clinical features. Method: In our present research, we retrospectively collected 731 patients who were diagnosed as CRC from Sun Yat-sen University Cancer Center, with ages lower than 70. All of them received genetic mutation detection consisting of a set of 14 specific inherited genes, which used target area capture and the second-generation high throughput sequencing technology. The characteristics of he patients with or without mutations were compared. We applied several comparison analysis to investigate the germline mutations distribution of genes that associated with the defined hereditary CRC syndromes in Chinese cohort. Results: 397 patients (54.3%) harbored functionally variants of the 14 genes in CRC patients that diagnosis lower than 70. Intriguingly, we observed no statistical difference for clinical factors such as age, sex, smoke, drink, family history, pathology grade, clinic stage and overall survival between groups. In Mut group, the mutation frequency of each genes are MLH1(21.4%), MSH2(17.6%), MSH6(15.1%), PMS2(9.3%), EPCAM(8.3%), MLH3(8.1%), AXIN2(7.1%), PMS1(4.0%), MUTYH(12.8%), APC(12.3%), STK11(3.5%), BMPR1A(1.8%), SMAD4(0.3%), PTEN(1.0%). Genome mutual exclusivity analysis has identified a set of genes such as MLH1, MSH2, MUTYH, MSH6, APC and PMS2, for which most pairwise combinations are found rarely cooccurred. In correlation analysis between mutational genes and clinical features, pathology grade correlates strongly with PMS1 and SMAD4(P&amp;lt;0.05). Tumor location correlates strongly with APC, MLH1, MSH2 and MSH6(P&amp;lt;0.05). In mutation group, the ratio of Lynch syndrome and non-Lynch is 76.8% and 23.2%, respectively. Conclusion: The clinic features of two groups have no statistic difference, which suggested other genes undiscovered may play a partial role in pathogenesis of patients of non-MUT group. In summary, we conducted a retrospective study to lead a comprehensive comparison of mutational profiles between MUT and non-MUT hereditary CRC patients, which supplemented the limited data of hereditary CRC in China. Citation Format: Feng Wang, Qi Zhao, Teng-jia Jiang, Ying-nan Wang, Fu-rong Liu, Jia-jia Hu, Pei-rong Ding, Zhi-zhong Pan, Jian-yong Shao, Rui-hua Xu. Germline mutational profileof Chinese patients with colorectal cancer and diagnosed lower than 70 years [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4161.

Principles of Diagnosis and Personalized Treatment of Hereditary Colorectal Cancer

The most frequent forms of hereditary colorectal cancer syndromes are Lynch syndrome and familial adenomatous polyposis (FAP). All the patients with suspicion to these syndromes need precise clinical and genetic diagnostics. Affected patients need personalized program of treatment because standard algorithm cannot be considered sufficiently effective. Identification of a pathogenic mutation in a patient indicates the need for DNA diagnostics in his close relatives and only in this case all the carriers of pathogenic germline mutations can be included in the high-risk group. Algorithms of clinical monitoring and operative treatment for mutation carriers were developed in different countries. However, different populations have their own genetic and clinical features. The aim of this work was to highlight the principles of diagnosis and personalized treatment of patients with hereditary colorectal cancer, taking into account international and Russian recommendations.

Su1031 – Prevalence of Germline Mutations and Variable of Uncertain Significance (VUS) Among Hispanics with Suspected Hereditary Colorectal Cancer Syndromes

Su1031 – Prevalence of Germline Mutations and Variable of Uncertain Significance (VUS) Among Hispanics with Suspected Hereditary Colorectal Cancer Syndromes

Adherence to post-polypectomy surveillance guidelines: a systematic review and meta-analysis.

Colorectal cancer (CRC) is a major worldwide cause of cancer-related mortality. Colonoscopy programs based on guideline-recommended surveillance intervals have been put in place to reduce the morbidity and mortality associated with CRC. We were interested to evaluate clinical practice adherence to guideline-recommended surveillance intervals, the potential extent of early repeat colonoscopies, and causes of nonadherence to guideline recommendations. We performed a literature search for articles reporting on guideline adherence for surveillance colonoscopies. Exclusion criteria included inflammatory bowel disease and hereditary CRC syndrome cohorts. Primary outcome was correct interval assignment in patients undergoing surveillance colonoscopy. Groups were assessed for adherence according to their respective guideline recommendations (North American or European). 16 studies were included in the analysis. The mean colonoscopy surveillance interval adherence rate was 48.8 % (95 % confidence interval [CI] 37.3 - 60.4). For North American guidelines, surveillance interval assignments were adherent to guideline recommendations in 44.7 % (95 %CI 24.2 - 66.3) of patients after detection of low risk lesions and in 54.6 % (95 %CI 41.4 - 67.4) after detection of high risk lesions. For European guidelines, surveillance interval assignments were adherent to recommendations in 24.4 % (95 %CI 1.1 - 63.4) of patients after detection of low risk lesions and in 73.6 % (95 %CI 35.5 - 98.8) after detection of high risk lesions. The worldwide adherence to surveillance colonoscopy guidelines was low, with more than 50 % of patients undergoing repeat colonoscopies either too early or too late. Early repeat colonoscopies occurred with the highest frequency for patients in whom only hyperplastic polyps or low risk adenomas were found.

Single-center study of Lynch syndrome screening in colorectal polyps

BackgroundLynch syndrome is the most common hereditary colorectal cancer syndrome, and adenoma is one of the important premalignant lesions to colorectal cancer in Lynch syndrome. The first objective of this study was to calculate the detection rate of Lynch syndrome in colorectal polyps by using mismatch repair immunohistochemistry as the initial screening strategy. The second objective of this study was to optimize screening strategies for adenoma associated with Lynch syndrome by integrating polyp and/or patient characteristics such as polyp size, location, dysplasia, age of onset and/or family history of cancer.MethodsFrom June 2014 to May 2016, immunohistochemistry was performed for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) using endoscopically resected specimens obtained from newly diagnosed colorectal adenomas. Gene analysis was performed in patients with missing expression of mismatched repair protein.ResultsFive hundred and ten patients underwent colorectal polyp resection, with a total of 718 polyps. Five hundred and eight resected adenomas underwent mismatch repair protein immunohistochemical testing. Loss of mismatch repair protein expression was observed in six adenomas, accounting for 1.18% of all adenomas. Five patients then underwent genetic tests to identify two pathogenic mutations from different individuals, while another patient was suspected to have a pathogenic mutation. Three patients were younger than 50 years old. Two patients had advanced histology (high-grade dysplasia and malignant components) and one patient had a family history of cancer.ConclusionImmunohistochemical detection of colorectal polyp mismatch repair protein as Lynch syndrome screening efficiency is low. Effective screening strategies may be improved by optimizing patient/polyp selection, such as focusing on young adenoma patients with a family history of cancer, or patients who present with high-risk features (large size, villous, high-grade dysplasia and malignant components).

Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.

Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.

Hereditary colorectal cancer diagnostics in southern Sweden: retrospective evaluation and future considerations with emphasis on Lynch syndrome

Overlapping phenotypes between different hereditary colorectal cancer (CRC) syndromes together with a growing demand for cancer genetic testing and improved sequencing technology call for adjusted patient selection and adapted diagnostic routines. Here we present a retrospective evaluation of family history of cancer, laboratory diagnostic procedure, and outcome for 372 patients tested for Lynch syndrome (LS), i.e., the single most common hereditary cause of CRC. Based on number of affected family members and age at cancer diagnosis in families with genetically confirmed LS, we developed local patient selection criteria for a simplified one-step gene panel mutation screening strategy targeting also less common Mendelian CRC syndromes. Pros and cons of this strategy are discussed.

The Zinc Linchpin Motif in the DNA Repair Glycosylase MUTYH: Identifying the Zn2+ Ligands and Roles in Damage Recognition and Repair.

The DNA base excision repair (BER) glycosylase MUTYH prevents DNA mutations by catalyzing adenine (A) excision from inappropriately formed 8-oxoguanine (8-oxoG):A mismatches. The importance of this mutation suppression activity in tumor suppressor genes is underscored by the association of inherited variants of MUTYH with colorectal polyposis in a hereditary colorectal cancer syndrome known as MUTYH-associated polyposis, or MAP. Many of the MAP variants encompass amino acid changes that occur at positions surrounding the two-metal cofactor-binding sites of MUTYH. One of these cofactors, found in nearly all MUTYH orthologs, is a [4Fe-4S]2+ cluster coordinated by four Cys residues located in the N-terminal catalytic domain. We recently uncovered a second functionally relevant metal cofactor site present only in higher eukaryotic MUTYH orthologs: a Zn2+ ion coordinated by three Cys residues located within the extended interdomain connector (IDC) region of MUTYH that connects the N-terminal adenine excision and C-terminal 8-oxoG recognition domains. In this work, we identified a candidate for the fourth Zn2+ coordinating ligand using a combination of bioinformatics and computational modeling. In addition, using in vitro enzyme activity assays, fluorescence polarization DNA binding assays, circular dichroism spectroscopy, and cell-based rifampicin resistance assays, the functional impact of reduced Zn2+ chelation was evaluated. Taken together, these results illustrate the critical role that the "Zn2+ linchpin motif" plays in MUTYH repair activity by providing for proper engagement of the functional domains on the 8-oxoG:A mismatch required for base excision catalysis. The functional importance of the Zn2+ linchpin also suggests that adjacent MAP variants or exposure to environmental chemicals may compromise Zn2+ coordination, and ability of MUTYH to prevent disease.

Management of small bowel and pouch neoplasia in hereditary colorectal cancer syndromes

Small bowel and pouch neoplasia remains an important, yet commonly overlooked, disease process in patients with familial colorectal cancer syndromes. The aim of this paper is to summarize the incidence and management of small bowel neoplasia in the more common syndromes, and outline recommendations for management and surveillance

Cancer prevention in hereditary colorectal cancer syndromes: Chemoprevention and lifestyle changes

Lynch Syndrome (LS) and familial adenomatous polyposis (FAP) represent the most prevalent inherited colorectal cancer syndromes. The key to reducing morbidity and mortality in affected individuals is prevention, and there is interest in chemopreventive agents that can either delay or prevent the need for procedural or surgical interventions. Sulindac is supported as a chemopreventive agent for the reduction of colorectal and duodenal polyps, as well as desmoids, in FAP. Aspirin has shown benefit in reducing polyp burden in LS. Modifiable lifestyle and diet-related risk factors are considered in reference to those with inherited colorectal cancer syndromes. We also emphasize the value of adherence to screening guidelines with the aid of registries as a powerful preventative strategy in the care of these high-risk patients.