Abstract 1683: Mutational landscape of colorectal cancer with POLE gene mutation
Authors: Inoue Yoshikage , Kakiuchi Nobuyuki , Yoshida Kenichi , Shiozawa Yusuke , Shiraishi Yuichi , Chiba Kenichi , Yoshizato Tetsuichi , Tanaka HIroko , Nagayama Satoshi , Miyano Satoru , Sakai Yoshiharu , Ogawa Seishi 
Published: August 2019

Abstract
Introduction
POLE-mutated tumor is a rare subtype of colorectal cancer (POLE-CRC) and 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.
Methods
We included a total of 3,240 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, either by targeted-panel sequencing (n=544) or amplicon-based deep sequencing (n=2,696). POLE mutation-positive samples were further analyzed by whole exome sequencing.
Results
In total, 74 POLE variants were detected in 69 samples, of which 40 showed prominent hypermutation (median; 5,346, range; 837-16,990) with the predominance of COSMIC signature 10 associated with defective POLE functions. Patients with POLE-CRC were significantly younger (median; 50, range; 33-84), compared with those with non-hypermutated CRC (median; 65, p-value&lt;0.01) and MSI-CRC (median; 70, p-value&lt;0.01). They also showed significantly favorable prognosis than patients with non-hypermutated CRC (p-value&lt;0.01). In accordance with previous reports, mutational hotspots in POLE gene were found at codons 411, 286, 459, and 456, while a previously unreported variant was found in 1 case, which affected an active site of the exonuclease domain on codon 277. Significantly mutated genes or driver genes in 40 POLE-CRC cases were interrogated by evaluating non-synonymous vs. synonymous mutations in each gene, using dNdSCV. We found 9 genes showing significantly deviated dN/dS (q-value&lt;0.1), including B2M, APC, TP53, PTEN, PIK3CA, PIK3R1, ARID1A, TAP1, and CD58 of which most frequently observed was APC (39/40; 97.5%). Of interest, two of these genes, B2M and TAP1, are involved in the antigen presentation machinery (APM). When samples having truncating mutations in HLA-A, B, C, and TAP2 are included, 70% (28/40) of POLE-CRC samples are thought to have compromised neoantigen presentation. Positive selection of mutations in APM was also found in our analysis of POLE-mutated endometrial cancer. Because of an extremely heavy burden of somatic mutations in POLE-mutated cancers, this finding suggested an important role of anti-cancer immune evasion in the pathogenesis of these POLE-mutated cancers. Also of note is frequent loss-of-function mutations in CD58, a molecule involved in NK-cell recognition. In 70% (7/10) of CD58 mutated cases, co-occurrence with mutations affecting the APM was detected. Loss of intact CD58 might play a role in the evasion from NK cell surveillance for tumors with defective HLA presentation.
Conclusions
Similar to MSI-CRC, POLE-CRC shows a favorable prognosis, where the mutations affecting APM are positively selected to evade immune surveillance, suggesting a possible role of checkpoint blockade in its therapeutics.
Citation Format: Yoshikage Inoue, Nobuyuki Kakiuchi, Kenichi Yoshida, Yusuke Shiozawa, Yuichi Shiraishi, Kenichi Chiba, Tetsuichi Yoshizato, HIroko Tanaka, Satoshi Nagayama, Satoru Miyano, Yoshiharu Sakai, Seishi Ogawa. Mutational landscape of colorectal cancer with POLE gene mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1683.