Abstract 2745: Exome sequencing analysis of 41 patients with Familial Colorectal Cancer Type X (FCCTX)
Authors: Melas Marilena , Luu Hung N. , Rennert Gad , Lejbkowicz Flavio , Gruber Stephen B. , Wiesner Georgia L. , Raskin Leon 
Published: August 2015

Abstract
Colorectal cancer (CRC) is the second most common cancer. About 10% of CRC are hereditary including familial adenomatous polyposis (FAP), hereditary non-polyposis colorectal cancer (HNPCC), and rare syndromes. While genetics of FAP and rare syndromes is well studied (APC, STK11, AXIN2), only ∼40-50% of HNPCC have identifiable DNA mismatch-repair gene defects. CRC cases fulfilling Amsterdam Criteria I for HNPCC with normal DNA mismatch repair and elevated risk of microsatellite-stable CRC are called Familial Colorectal Cancer Type X (FCCTX). Compared to HNPCC, FCCTX patients are older, with left-sided CRC, and frequent polyps. We hypothesize that FCCTX is a dominant Mendelian cancer syndrome with incomplete penetrance caused by rare, family-specific mutations in oncogenes and tumor suppressors.
To identify novel mutations and genes involved in FCCTX, we performed germline exome sequencing of microsatellite-stable familial CRC from Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based, case-control CRC study in Northern Israel. We selected 41 patients from 38 FCCTX families with extensive family history of microsatellite stable (MSS) or microsatellite instable low (MSI-Low) CRC. Patients were Ashkenazi Jewish, Sephardi Jewish, Europeans, Druze, and Arabs. Similar to previous studies, stomach cancer was second most common in the families, and left-sided CRC was more prevalent.
Exome sequencing of all patients generated 52,722 variants. Stepwise filtering analysis was applied to identify candidate variants and genes. We selected all novel and rare (minor allele frequency &lt;0.001) functional variants in cancer-related genes from literature and cancer databases (COSMIC and TCGA). In line with dominant inheritance, only heterozygous variants predicted to be deleterious by multiple bioinformatic tools were selected. We identified 627 variants in 387 genes. Gene enrichment analysis showed regulation of apoptosis and cell cycle, DNA repair, cell adhesion, and cell surface receptor linked signal transduction.
As expected, we found APC*I1307K founder mutation in three Ashkenazi Jewish patients, one novel APC mutation (p.1289_1291del) in a non-Jewish European patient, and found a mutation in MSH6. We identified three promising candidate genes and performed segregation analysis in families. Our preliminary data suggest several novel candidate genes for FCCTX, although older age at onset and incomplete penetrance complicate the interpretation of the results. Further population-based and family-based studies are being conducted to confirm our findings.
Citation Format: Marilena Melas, Hung N. Luu, Gad Rennert, Flavio Lejbkowicz, Stephen B. Gruber, Georgia L. Wiesner, Leon Raskin. Exome sequencing analysis of 41 patients with Familial Colorectal Cancer Type X (FCCTX). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2745. doi:10.1158/1538-7445.AM2015-2745