Abstract 5873: Distinct prevalence and spectrum of germline cancer susceptibility gene mutations between early-onset and late-onset colorectal caner

Abstract Background: In the past few decades, the incidence of early-onset CRC (<50 years of age) has increased globally. Previous studies with small sample sizes have shown that early-onset CRC appears to have a distinct clinical, pathologic, and molecular features compared to late-onset CRC (≥ 50 years of age). However, few studies in a large population have focused on the differences in germline gene mutation spectrums of these two groups of patients. Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in 5080 colorectal patients in a CAP/CLIA-approved laboratory (3DMed). NGS testing for germline mutations and MSI was implemented. Results: Of 5080 colorectal patients, early-onset CRC was observed in 1305 (25.7%) patients. The incidence of germline mutation was higher in early-onset CRCs than late-onset CRCs (8.97% vs. 4.15%,OR=2.27, P<0.0001). Consistently, the frequency of MSI-H was higher in early-onset CRCs (13.0% vs. 5.7%, OR=2.48, P<0.0001). The most frequently mutated gene was MLH1 (3.07%) in early-onset CRCs, followed by MSH2 (1.69%), APC (1.0%), MSH6 (0.84%), PMS2 (0.38%), RAD50 (0.31%), CHEK2 (0.31%), MUTYH (0.23%), BRCA1 (0.23%), and BRCA2 (0.23%). The frequency of MMR gene mutations among early- and late-onset patients was 5.98% and 1.27%, respectively (OR=4.95, P<0.0001). MMR gene mutations accounted for 60% of germline mutations of early-onset patients, while this percentage was lower for late-onset CRC (30%). Higher frequencies of APC, RAD50 and CHEK2 gene mutations were associated with early-onset CRCs (all P<0.05). The mutation frequencies of other DDR genes, MUTYH, BRCA1, BRCA2, ATM, ATR, FANCD2, TP53, were not statistically different between the two groups. The late-onset CRC tended to harbor a wider spectrum of germline cancer gene mutations, including an additional 14 cancer-related gene that were not found in early-onset CRC. Conclusions: Our findings revealed different prevalence and spectrum of germline cancer gene mutations between early-onset and late-onset CRC, suggesting that young patients should be specially considered. Citation Format: Zhidong Gao, Jing Zhou, Ying Xin, Bin Liang, Kai Shen, Peng Guo, Kewei Jiang, Mujun Yin, Xiaodong Yang, Zhanlong Shen, Hui Zhang, Depei Huang, Yingjiang Ye. Distinct prevalence and spectrum of germline cancer susceptibility gene mutations between early-onset and late-onset colorectal caner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5873.