Abstract 3547: Frequent genomic alterations to evade the immune system in colorectal cancer with POLE gene mutation
Authors: Inoue Yoshikage , Kakiuchi Nobuyuki , Yoshida Kenichi , Takeuchi Yasuhide , Shiozawa Yusuke , Shiraishi Yuichi , Chiba Kenichi , Yoshizato Tetsuichi , Tanaka Hiroko , Okada Ai , Nagayama Satoshi , Miyano Satoru , Sakai Yoshiharu , Ogawa Seishi 
Published: September 2020

Abstract
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&lt;0.01) and MSI-CRC (median of 70 years, p&lt;0.01). They also showed a significantly favorable prognosis than non-hypermutated CRC patients (p&lt;0.01). Driver genes in 44 POLE-CRC cases were investigated using dNdSCV. A total of 9 genes showed significantly deviated dN/dS (q-value&lt;0.01), of which APC (43/44; 97.7%) was most frequently mutated, followed by PIK3R1, PIK3CA, PTEN,TP53, ARID1A, B2M, TAP1 and CD58. Among these, two genes, B2M and TAP1 are components of the antigen presentation machinery (APM). We also found frequent LOH (8/44; 18%) affecting the 6p arm, containing HLAs, TAP1 and TAP2, also suggesting the role of compromised APM. Functional impact of core genetic events was investigated by immunohistochemistry of HLAs, B2M, TAP1 and TAP2. All samples with B2M biallelic mutations showed complete loss of B2M and HLAs. All samples with TAP1 biallelic mutations showed complete loss of TAP1 and TAP2 even with intact HLA expression, suggesting a defect in the loading of antigens onto HLAs. Also of note is frequent loss-of-function mutations in CD58, a molecule involved in NK-cell recognition. Loss of intact CD58 might play a role in the evasion from NK-cell surveillance for tumors with defective HLA presentation. Altogether, 75% (33/44) of POLE-CRC harbored alterations to evade the immune system though loss of relevant HLA or APM components as well as CD58.
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.