Israel Medical Association Journal

Background: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative for APC gene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16.

Objectives: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol.

Methods: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to ≥ 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC[1] patients fulfilling “Bethesda” (laboratory investigation) criteria for Lynch syndrome.

Results: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI²-High with immunohistology consistent with MLH1 mutation.

Conclusions: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.

Pancreatic cancer is not a common malignancy in Israel, but it is the third most common cause of cancer mortality, attributable to a lack of screening tests, inaccessibility of the pancreas, and late cancer stage at diagnosis. We reviewed the epidemiology, known risk factors and screening methods available in Israel and describe the Israeli national consortium that was established to identify persons at risk and decide on screening methods to detect and treat their early-stage pancreatic cancer. In collaboration with the Israel National Cancer Registry, we evaluated the incidence and trends of the disease in the Jewish and non-Jewish populations. The consortium reviewed known lifestyle risk habits and genetic causes, screening methodologies used and available in Israel. Overall, there are about 600 new patients per year, with the highest incidence occurring in Jewish men of European birth (age-standardized rate 8.11/10⁵ for 2003–06). The 5 year survival is about 5%. The consortium concluded that screening will be based on endoscopic ultrasonography. Pancreatic cancer patients and families at risk will be enrolled, demographic and lifestyle data collected and a cancer pedigree generated. Risk factors will be identified and genetic tests performed as required. This concerted national program to identify persons at risk, recommend which environmental risk factors to avoid and treat, and perform endoscopic ultrasound and genetic screening where appropriate, might reduce their incidence of invasive pancreatic cancer and/or improve its prognosis