The Significance of Somatic Variants Involved in the Development of Pancreatic Cancer in Patients with HBOC-Associated Germline Variants.

BACKGROUND: Hereditary cancer predisposition syndromes show a high risk of cancer development with germline pathogenic variants. Organ-specific surveillance has been recommended according to the causative gene. However, even among carriers of the same germline variants, developing cancer types are not always uniform. Tumor-normal paired comprehensive genomic profiling (CGP) enables the simultaneous assessment of germline and somatic variants in same patient. Correlations between germline variants and cancer types have been reported; however, the significance of combinations of a germline variant and somatic variants remain unclear in the development of cancer types. METHODS: In this study, we analyzed the correlation between pancreatic cancer and somatic variant patterns in patients with hereditary cancer predisposition syndrome, especially in patients with germline variants on BRCA1, BRCA2, or ATM. RESULTS: Here, we show the characteristic pancreatic cancer patterns according to co-existing somatic variants in patients with germline pathogenic variants. The tumor-normal paired genetic data from 18,732 patients who underwent tumor-normal paired CGP were analyzed, including 853 germline-positive patients registered in a Japanese database. The combination of the somatic TP53 variant and KRAS variant was closely correlated with the development of pancreatic cancer in patients with germline BRCA1, BRCA2, or ATM. In particular, the somatic KRAS variant was significantly associated with pancreatic cancer. CONCLUSIONS: These findings suggest that pancreatic cancer of hereditary cancer syndromes might be associated with co-existing somatic KRAS variants within the pancreas.