Abstract 3540: Germline mutation landscape of DNA damage repair genes in Oriental pancreatic cancer
Authors: Guo Shiwei , Jiang Lisha , Shi Xiaohan , Gao Suizhi , Li Bo , Lin Ling , Yu Jun , Jin Gang 
Published: September 2020

Abstract
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is recognized as the most lethal solid malignancies with very few therapeutic options. Until very recently, FDA approved the first molecularly targeted therapy with the PARP inhibitor Olaparib for pancreatic cancer patients with germline mutations on BRCA1/2, two types of homologous recombination (HR)/DNA damage repair (DDR) genes. In addition, the sensitivity of platinum-based chemotherapy and anti-PD-1 antibodies have been connected with DDR spectrum. However, the genetic landscape of PDAC is mainly based on data from Caucasian population. In this study, we sought to explore the germline mutation spectrum of DDRs in oriental PDAC for clinical practice.
METHODS
Germline DNA extracted from 256 Asian peri ampullary cancer patients (201 PDAC, 20 adenosquamous carcinoma, and 35 vater periampullary carcinoma) underwent whole exome sequencing. The mean depth of sequencing was 67 X. 229 DDR genes were focused for variant callings using the GATK and its pathogenicity according to the guidelines from ACMG. Pathogenic or likely pathogenic(P/LP) were further analyzed.
RESULTS
Pathogenic variants were identified in 26 of 256 patients (10.2%),and one patient had mutations in two genes. The 27 pathogenic mutations occurred in 16 different genes,including ERCC2 (n=4), OGG1 (n=4), PALB2 (n=3), FAN1 (n=3), RAD54L (n=2), WRN (n=1), POLH (n=1), MUTYH (n=1), MSH6 (n=1), MLH3 (n=1), LIG1 (n=1), ERCC6 (n=1), CHEK2 (n=1), BRCA2 (n=1), BRCA1 (n=1), and ATM (n=1). The detailed gene profiles were mainly involved in five pathways, Homologous recombination(HR), Fanconi anemia(FA), Mismatch repair(MMR), Base excision repair(BER)and Nucleotide excision repair(NER. Of note, two mutations MSH6 c.261-1G&gt;A and BRCA2 c.3912_3916del, were first reported to be associated with cancer and classified as likely pathogenic owing to their frameshift variant or splice site and low frequencies of occurrence. To determine the difference of germline DDR mutation landscape between oriental and American populations, we compared our cohort with American cohorts from Yurgelun and TCGA. The BRCA1/2 germline mutations were found at low levels in our cohort (0.8%) compared to the American cohorts (2.4~2.7%), Furthermore, the whole DDR mutations exhibited highest proportion [10.5% (27/256) from our study, compared with 7.3% (21/289) from Yurgelun, and 5.4% (10/185) from TCGA, respectively].
CONCLUSION
In conclusion,our results characterized the germline mutation landscape of DDRs in the largest oriental cohort of pancreatic cancer to date, and first discovered two novel germline mutations in pancreatic cancer. Most importantly, nearly 10% of PDAC patients in this study were found to harbor germline DDR mutations, which may benefit more patients with an effective therapeutic synergy for PARP and PD-1 inhibitors in clinical practice.
Citation Format: Shiwei Guo, Lisha Jiang, Xiaohan Shi, Suizhi Gao, Bo Li, Ling Lin, Jun Yu, Gang Jin. Germline mutation landscape of DNA damage repair genes in Oriental pancreatic cancer [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 3540.