Abstract 3547: Frequent genomic alterations to evade the immune system in colorectal cancer with POLE gene mutation

Introduction POLE-mutated tumor is a rare subtype of colorectal cancer (POLE-CRC), whose pathogenesis has been poorly understood because of its rarity. In this study, we have investigated the clinical and genetic features of POLE-CRC in the largest cohort of this unique subtype of CRC ever analyzed. Methods We included a total of 3,265 patients who had been treated at the Cancer Institute Hospital of Japanese Foundation for Cancer Research between 2004 and 2017, which were screened for POLE mutations by targeted-panel sequencing. The POLE-mutated samples were further analyzed by whole exome sequencing. All samples were well-annotated for clinical information. Results In total, 44 samples showed prominent hypermutation with a median of 5,346 (range: 837-16,990) with the predominance of COSMIC signature 10 associated with defective POLE functions. By contrast, copy number variations (CNV) in POLE-CRC was much less common compared to non-hypermutated CRC. In accordance with previous reports, mutational hotspots in the POLE gene were found at codons 411, 286, 459, and 456. Patients with POLE-CRC were significantly younger (median of 50 years), compared with non-hypermutated CRC (median of 65 years, p Conclusions POLE-CRC is a CRC subtype with a favorable prognosis compared with other CRC subtypes and is characterized by high frequency of genetic alterations affecting APM, which is implicated in immune evasion of this unique subtype of CRC with an extremely high mutational burden. Citation Format: Yoshikage Inoue, Nobuyuki Kakiuchi, Kenichi Yoshida, Yasuhide Takeuchi, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Tetsuichi Yoshizato, Hiroko Tanaka, Ai Okada, Satoshi Nagayama, Satoru Miyano, Yoshiharu Sakai, Seishi Ogawa. Frequent genomic alterations to evade the immune system in colorectal cancer with POLE gene mutation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3547.