Hana Strul

The Prevalence Rate and Anatomic Location of Colorectal Adenoma and Cancer Detected by Colonoscopy in Average-Risk Individuals Aged 40–80 Years

BACKGROUND:The role of screening colonoscopy for colorectal (CR) neoplasia in average-risk population, remains to be determined.OBJECTIVES:To evaluate the prevalence and anatomic location of CR adenoma and carcinoma and the morbidity of colonoscopy in individuals at average risk for CR cancer (CRC).METHODS:A retrospective prevalence study of subjects aged 40–80 yr, with no cancer-related symptoms, personal or family history of CR neoplasia, who underwent a colonoscopy.RESULTS:Enrolled were 1,177 persons; 183 aged 40–49 yr (young), 917 aged 50–75 yr, and 77 aged 76–80 yr (elderly). The prevalence of overall CR neoplasia, advanced neoplasia, and cancer was 20.9%, 6.3%, and 1.1%, respectively. In the 50–75 age group, the prevalence of overall adenoma, advanced neoplasia, and cancer was 21.3%, 6.7%, and 1.2%, respectively. Of the 206 neoplasia cases, 21–43% harbored proximal neoplasia beyond the reach of sigmoidoscopy, without distal lesions. Among the elderly, the prevalence of overall adenoma, advanced neoplasia, and cancer reached 26.0%, 14.3%, and 2.6%, respectively. In the young group, 9.8% had overall neoplasia, 1.1% had advanced adenoma, and none had CRC. Procedure-related morbidity rate was 0.1%, with no perforations, bleedings, or mortality.CONCLUSIONS:Screening colonoscopy in average-risk subjects demonstrated a considerable prevalence of CR neoplasia and proximal lesions beyond the reach of sigmoidoscopy. The morbidity rate was negligible. Primary screening colonoscopy should be considered in health programs for the average-risk population, beginning at the age of 50 yr. The significantly high rate of advanced and proximal neoplasia in the elderly, encourages the inclusion of healthy subjects aged 76–80 yr in future prospective studies.

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC.

Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.

Determinants of adherence to screening by colonoscopy in individuals with a family history of colorectal cancer

OBJECTIVE Although first-degree relatives (FDRs) of colorectal cancer (CRC) patients, as a high-risk population, have the most to gain from colonoscopy screening, their adherence is suboptimal. Thus, an assessment of the determinants of adherence to screening is of potential importance. METHODS A cross-sectional study was conducted among 318 FDRs of 164 CRC patients treated at Tel-Aviv Sourasky Medical Center. Interviews were conducted with a questionnaire using I-Change Model. RESULTS Adherence to interval colonoscopy was low with only 73 FDRs (23.0%). Greater adherence was associated with socio-demographic variables (older age, siblings, having spouse, higher level of education and income) and behavioral variables (healthier lifestyle, utilization of preventive health services). Family physicians and kin were identified as the most influential figures on uptake. Intention, affective barriers, positive attitudes, social support, cues to action, age, and health maintenance were the strongest determinants of participation in CRC screening. CONCLUSION Adherence to colonoscopy is determined by multiple variables. Medical staff can play a key role in increasing adherence to colonoscopy. PRACTICE IMPLICATIONS Future interventions should focus on fostering positive attitudes, overcoming barriers, enhancing social support and providing a medical recommendation. Special efforts should be invested in young FDRs, those of low socio-economic status and those who underutilize preventive medicine.

Genetic features of Lynch syndrome in the Israeli population

Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high‐risk clinics. Diagnostics followed a multi‐step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty‐seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR‐D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR‐D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.

Tu1893 MUTYH Mutations and Variants in Jews of North-African Origin With or Without Minimal Colorectal Adenomatous Polyposis

Background: Israeli-Jews of North-African origin are ~ 1/6 of the Israeli population, and have been considered as a low-risk population for colorectal cancer (CRC). In recent years CRC risk has been increased in this population. However, the contributing genetic susceptibility is currently unknown. Mutations in the MUTYH gene, which cause multiple colorectal adenomas and early onset colon cancer, might play a role in their increased CRC risk. Objectives: Evaluate frequency and types of MUTYH mutations and variants in a population of Jews fromNorth-African origin having colorectal adenomas and early onset CRC. Methods: The study population included North-African Jews having colonoscopy between 2007-12, having ≥3 colorectal adenomas and/or CRC, and were matched to controls having normal colonoscopy. Germ-line DNA was tested for a panel of 6 MUTYH mutations or variants and Sanger sequencing of the entire MUTYH gene for heterozygotes. Familial Adenomatous Polyposis (FAP) and Lynch Syndrome were excluded in the relevant cases. Results: 99 subjects, 69 with adenomas had MUTYH analysis; 19 (27.5%) had mutations or variants identified. In adenoma patients there were eight homozygotes or compound heterozygotes to either Y179C or G396D mutations: all had >10 adenomas and 5 had familial neoplasia. Six others were heterozygotes to only one mutation: 4 with 10 adenomas; 5 had familial neoplasia and 3 a neoplasm. Four subjects found as S512F heterozygotes: two had 10 adenomas. Two heterozygotes had the Q324H variant. In 23 non-adenoma controls: 1 had the S512F another the L417M variant, another the R509C variant and 16 the Q324H variant. Conclusions: MUTYH mutations are prevalent among Jews of North-African origin having colonic adenomas and/or early onset CRC. The clinical phenotype can be associated with only few adenoma and with family and personal history of cancer similar to sporadic CRC. The S512F mutation appears to be pathogenic, the Q324H a frequent variant that was not found to be associated with adenomas. The findings suggest MUTYH evaluation in these patients with even few adenomas, and need to follow-up heterozygotes carriers for CRC.