Abstract 5778: Early age of onset of double germline DDR-mutated gastric cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2022-06, Vol.82 (12_Supplement), p.5778-5778
• Main Authors: Qu, Yurong, Shi, Min, Liang, Yiming, Zhu, Bowen
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2022-5778

Background: Gastric cancer (GC) is one of the leading causes of cancer death in China. Approximately 10% of GC cases are associated with strong familial clustering and can be attributed to genetic predisposition. However, GC is biologically and genetically highly heterogeneous, the underlying genetic cause is complicated. DNA damage repair (DDR) genes play key roles in maintaining human genomic stability. Loss of DDR function, conversely, is an important determinant of cancer risk, progression, and therapeutic response.Our aim was to analyze the germline mutational pattern of DDR-mutated Chinese GC cohort and find possible genetic factors related to the early onset of gastric cancer. Methods: In this analysis we defined a “core DDR” gene set with 10 homologous recombination deficiency-HRD gene (BRCA1, BRCA2, ATM, PALB2, BRIP1, CDK12,CHEK1, CHEK2,FANCA and FANCL) and 4 mismatch repair-MMR gene (MLH1,MSH2,PMS2 and PMS6). The panel of 14 core DDR genes was used to analyze the germline mutation profiling of DDR-mutated GC cohort which is consisted of 144 Chinese patients with at least one germline “core DDR” gene likely pathogenic/pathogenic (LP/P) mutations. LP/P mutations were called according to the classification criteria of the American College of Medical Genetics and Genomics. Results: The DDR-mutated GC cohort was consist with 144 patients with at least one “core DDR” gene germline mutations, and the median age of this cohort was 63 years. In this cohort, eighty-three of 144 patients carried only one HRD gene P/LP mutations (median age at onset:63), forty-two patients of 144 patients carried only one MMR gene P/LP mutation (median age at onset:65.5). Nineteen of 144 (13.2%) patients had two “core DDR” germline mutation, and the median age of these patients with double germline mutations was 49. The double DDR-mutated GC had a significantly younger median age of onset than one HRD-mutated GC (log-rank test, P =0.00746) as well as one MMR-mutated GC (log-rank test, P =0.00849). Three of the double DDR-mutated patients had family histories of gastrointestinal cancer. Conclusion: Our data suggests that GC patients harboring any two germline mutations in the “core DDR” gene may have an earlier age of onset. Citation Format: Yurong Qu, Min Shi, Yiming Liang, Bowen Zhu. Early age of onset of double germline DDR-mutated gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA