Sa1892 Dabigatran -Risk Factor of Severe Bleeding in Distal Esophagus in Elderly Women

Abstract

Background: Several driver mutations have been discovered in colorectal cancer (CRC) progression including KRAS and BRAF that have practical significant therapeutic and prognostic implications. Whole Exome sequencing (WES) is revolutionizing the screening for pathologic single nucleotide variants (SNV) in complex disorders such as CRC. Little or no studies have comprehensively examined the association between somatic genetic variants in signaling pathways and risk of CRC in African Americans (AA). Aim: To determine somatic variants that drive colorectal carcinogenesis in AA. Methods: WES was carried out on DNA from 12 normal-tumor pairs of frozen biopsies from AA CRC patients. Base call quality recalibration, realignment validation around Indels, SNV calling and variants' call recalibration were carried out using GATK (Genome Analysis Tool Kit), and normative population databases (e.g. 1000Genomes SNP database, dbSNP, andHapMap) that provide the capability to filter genetic variants from putative mutations. Variants were then annotated using Annova. Sanger sequencing was used for SNVs' validation. Results: WES uncovered somatic mutations in many genes that are known targets in CRC including APC, BRAF, KRAS, Notch1, PIK3CA, and NDRG4. We discovered a number of novel SNVs in EID3, RGS3, HNRNPF, GNAS and APC. We detected several rare and unique alterations in the known WNT pathway gene: APC. These SNPs included, NM_001127511.2:c.4378_4384del (APC4378), NM_ 001127511.2:c.4401delT (APC4401), NM_001127511.2:c.648_657del (APC648), and NM_001127511.2:c.3418A>T (APC3418) which consist of a, frame shift deletions for the first three SNPs, and one stop codon mutation for the fourth SNP. Three of these novel variants, namely APC4378, APC4401 and APC3418, are located in exon 15, the exon of which the mutations are highly associated with CRC risk. Conclusion: This first WES from