Abstract 3930: Targeted cancer gene sequencing identifies potential causative novel candidate mutations among Caucasian colon carcinogenesis

Abstract

Abstract Much of the sporadic colorectal cancer's (CRC) underlying genetic ‘cancer driver’ mutations are unknown in patients from specific ethnic groups. Here, we report the identification of distinct novel variants from adenoma and CRC patients in mismatch repair (MMR) genes MHS3 and MSH6, and in PIK3CA and APC. We developed a panel of 20 frequently altered colon cancer genes comprised of ACVR2A, APC, ARID1A, BRAF, FAM123B, FBXW7, KRAS, MSH2, MSH3, MSH6, NRAS, PIK3CA, POLE, PTEN, SMAD2, SMAD4, SOX9, TCF7L2, TGFBR2, and TP53 for targeted sequencing in 65 colon tissues, comprised of 1 normal tissue sample, 2 adenomas, and 63 tumors. Multiplex PCR and Ion Torrent sequencing was used to examine 98.8% of the targeted exons and splice junctions at a depth of sequencing that allowed for high confidence variant calling (most bases were covered by ≥ 500 reads). After alignment and variant calling, we annotated the variants with information from the 1000 Genomes Project, COSMIC, Polyphen2, and PFAM domain and transcription factor motifs. Excluding synonymous SNVs, 3 variants in adenoma, and 692 variants in tumors were detected. Two were known pathogenic variants (MSH6 p.R965H and APC p.R1432X). Novel variants (286, 244, and 115) were found in MMR genes (MSH6 and MSH3), APC, and PIK3CA, respectively. Most of the MMR (n = 98), APC (n = 128), and PIK3CA (n = 43) variants are deleterious. Notably, among the 63 CRC cases, [(29/61 = 46%) 46%) for MSH3, MSH6] [(19/63 = 30%) (30%) for PIK3CA] [31/63 = 49%) (49%) for APC)] carried likely deleterious MMR, PIK3CA and APC mutations, respectively, suggesting the value of a broad cancer gene panel. These finding further highlight the relevance of APC, PIK3CA genes in CRC onset but also the potential underestimation of the MSI-H in sporadic CRC as many of the novel mutations in MMR gens detected here were of a deleterious nature. Citation Format: Hassan Ashktorab, Michael Nickerson, Sudhir Varma, Pooneh Mokarram, fakhraddin Naghibalhossaini, Lee Moore, Joseph Boland, Sara Bass, Meredith Yeager, Wen-Yi Haung, Hassan Brim. Targeted cancer gene sequencing identifies potential causative novel candidate mutations among Caucasian colon carcinogenesis. [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 3930. doi:10.1158/1538-7445.AM2015-3930