Abstract 4385: Landscape of driver gene mutations in stage II and stage III colorectal cancer
Authors: Inoue Yoshikage , Kakiuchi Nobuyuki , Yoshida Kenichi , Shiozawa Yusuke , Shiraishi Yuichi , Chiba Kenichi , Kataoka Keisuke , Ueno Hiroo , Tanaka Hiroko , Nagayama Satoshi , Miyano Satoru , Sakai Yoshiharu , Ogawa Seishi 
Published: July 2017

Abstract
Introduction
Colorectal cancer (CRC) is the second leading cause of cancer death in Japan. The overall survival rate is approximately 85% and 70% for stage II and stage III CRCs, respectively, where over 45,000 deaths were ascribed to recurrence or metastasis. Survival benefit of adjuvant therapy is well defined only among stage III CRC patients, whereas that for stage II CRC patients remains modest, or according to recent reports, might be even deleterious among those with microsatellite instability (MSI). In an attempt to reveal the landscape of driver mutations in CRC and their association with clinical outcomes, we conducted targeted-capture sequencing of known driver mutations in stage II and III CRCs.
Methods
A total of 248 patients with stage II (n = 145) and stage III (n = 103) CRC, were enrolled. All patients were treated at a single institute between 2004 and 2016 and clinically well-annotated. Targeted-capture sequencing was performed using RNA baits designed for detection of oncogenic variants in 128 known driver genes in CRC. Additional baits for 1,605 SNPs, 7 introns and 18 microsatellites were also included to assess genome-wide copy numbers, fusion genes and MSI, respectively.
Results
The median age at diagnosis was 64 (32-95) with a median observation period of 1,460 days. Of the 101 patients with recurrence, 59 and 42 patients had stage II and III diseases, respectively. Sixty percent of stage III patients received adjuvant chemotherapy, whereas only 10% of stage II patients received adjuvant chemotherapy. The average depth of the targeted-capture sequencing was 909×. In total, 2,243 somatic mutations (median 5 per patient, range 0-106) were detected in 243 patients (97.9%). VTI1A-TCF7L2 translocation was identified in one sample. Except for a modest overrepresentation of TP53 mutations, frequency distribution of mutations was similar to those reported in previous reports, where APC (83%), TP53 (79%), KRAS (45%), and PIK3CA (18%) represented the most frequent mutational targets. Although none of these mutations were significantly associated with tumor recurrence or overall survival, we found that FBXW7 mutations had a positive correlation with tumor free survival. Twenty-one patients had more than 20 mutations, suggesting the presence of defects in DNA repair and/or replication. In fact, analysis of 18 microsatellites suggested the presence of MSI in 12 of the 21 samples (4%). The remaining patients with hypermutated cancer were explained by somatic mutations in POLE gene.
Conclusions
We revealed the landscape of driver mutations in Japanese patients with stage II and III CRC with their implication in clinical outcomes. Hypermutated samples accounted for 8% of the whole cohort, which were explained by MSI or replication errors due to somatic POLE mutations. Our findings help to understand the relationships between driver mutations and recurrence for CRCs after curative resection.
Citation Format: Yoshikage Inoue, Nobuyuki Kakiuchi, Kenichi Yoshida, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Keisuke Kataoka, Hiroo Ueno, Hiroko Tanaka, Satoshi Nagayama, Satoru Miyano, Yoshiharu Sakai, Seishi Ogawa. Landscape of driver gene mutations in stage II and stage III colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4385. doi:10.1158/1538-7445.AM2017-4385