Guy Rosner

Role of CYP2D6 polymorphism in predicting liver fibrosis progression rate in Caucasian patients with chronic hepatitis C.

Abstract: Objective: Previous studies have demonstrated that CYP2D6 polymorphism is associated with liver cirrhosis. The aim of the present study was to find out whether CYP2D6*4, the poor metabolizer allele can predict fibrosis progression rate.

Comparative Study of Two Cohorts of Newly Diagnosed Crohn's Disease Demonstrates Change in Therapeutic Strategies

Background: There has been a paradigm shift in the treatment of Crohns disease (CD) involving the rapid introduction of biologics and/or immunomodulators after diagnosis. We wished to assess whether this was applied to patients with newly diagnosed CD in a tertiary inflammatory bowel disease referral centre in Israel. Methods: Newly diagnosed CD patients were stratified into 2 groups: the early group was diagnosed between 2005 and 2007 and the late group was diagnosed between 2010 and 2012. Baseline demographics, medical and surgical treatments, disease course and complications during those 2 periods were analyzed. Results: Each group included 60 patients. Significantly higher rates of immunomodulators and biologics were administered to patients in the late group compared to the early group (81.7 and 36.7% compared to 56.7 and 18.3%, p = 0.004 and p = 0.021, respectively). On the other hand, steroid therapy was less prevalent in the late (36.7%) group compared to that of the early group (56.7%), p = 0.059. Medical and surgical CD outcomes, including exacerbations/hospitalizations and surgeries, were comparable for both groups. Conclusions: There was a change in treatment strategy between 2005-2007 and 2010-2012, as reflected in higher proportions of biologics/immunomodulators for patients with newly diagnosed CD. This was associated with a steroid-sparing effect.

291 Mutations in DNA Polymerase Genes (POLD1 & POLE) in Individuals Having Early-Onset Colorectal Cancer and/or Multiple Adenomas

Colorectal cancer (CRC) screening has been shown to reduce CRC incidence and mortality through the endoscopic detection and removal of colorectal adenomas. Still, these patients are at increased risk for developing metachronous adenomas or even cancer, with the recurrence rate reaching the 50%. The pleiotropic effects of higher levels of PGE2 contribute to key steps of cancer development, including cell proliferation, angiogenesis, invasiveness and migration, inhibition of apoptosis and immunosurveillance as a refletion of deregulation of ATP-binding cassete sub-family c member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) genes responsable for carrying PGE2 accross the membrane. To evaluate the influence of genetic polymorphisms in ABCC4 and SLCO2A1 on the risk and time for colorectal adenoma recurrence a retrospective case-cohort study was designed gathering 195 patients diagnosed with colorectal adenomas. Adenoma reccurence was defined has the diagnosis of an adenoma after a total normal colonoscopy at least one year after the initial diagnosis. Thirty-three tagSNPs were characterized using the MassARRAY iPLEX Gold technology based on multiplex amplification followed by mass-spectrometric product separation. Three tagSNPs were identified as susceptibility biomarkers for colorectal adenoma recurrence after a bootstrap analysis. The rs1131598GG homozygous genotype of SLCO2A1 gene was associated with an enhanced risk of 6.3 (95%CI:1.31-30.0, P=0.021). In contrast and under a dominant model of inheritance, the rs1751031 and rs9524821 polymorphisms in ABCC4 gene displayed a protective behaviour (OR=0.29, 95%CI:0.12-0.72, P=0.007 and OR=0.42, 95%CI:0.19-0.93, P=0.033, respectively). Furthermore, when stratifying patients considering the endoscopic findings at baseline colonoscopy, low-risk individuals carriers of rs2274403AA genotype in ABCC4 gene had a lower interval until recurrence (85 (29140) vs 122 (109-135), P=0.011) with 44% of metachronous tumors developing by 36 months (vs 23% for AG/GG). This study demonstrates for the first time the involvement of genetic variants in PGE2 transporters in colorectal adenoma recurrence. The incorporation of genetically-based approaches might allow an optimization of current risk models for the development of metachronous colorectal adenomas or even more advanced lesions possible laeding to a decrease in CRC burden and mortality.

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.