Abstract A02: Assessment of germline cancer predisposition genes in 392 unselected pancreatic cancer patients

Aim: To determine the prevalence of pathogenic germline mutations in known pancreatic cancer (PC) predisposition genes in an unselected PC cohort; identify clinico-pathological characteristics associated with gene carrier status; and analyse somatic genomic data for evidence of biallelic inactivation. Methods: Whole-genome (n = 184) and exome (n = 208) sequencing was performed on matched tumor-normal DNA pairs from 392 predominantly sporadic cases of PC. Pathogenic mutations were assessed in 13 cancer predisposition genes associated with PC risk (APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, TP53. Results: A total of 377 unique high confidence germline variants were observed in the 13 PC predisposition genes. 22 were classified as pathogenic and identified in 23/392 (5.9%) PC patients. The mutations occurred in BRCA2 (n=9), ATM (n=4), BRCA1 (n=3), PALB2 (n=3), CDKN2A (n=2) and one each in PMS2 and STK11. Truncating BRCA2 and PALB2 mutations were detected in 2 cases classified as familial PC. There was no significant difference in average age at diagnosis (67.9 vs 66.6, P = 0.5468), post-resection survival (20.3 vs 20.5 months, P = 0.9788), family history of malignancy (55.6% vs 40.5%, P = 0.2249) or personal history of malignancy (31.8% vs 15.0%, P = 0.0642) between those with and those without a pathogenic germline PC risk mutation. Patients harboring BRCA1, BRCA2 or PALB2 mutations were associated with an increased family history of breast or ovarian cancer (27.3% vs 6.3%, P = 0.0348). The second-hit mechanism could be assessed in tumors with >30% cellularity (n=16), of which 75% (7 BRCA2, 4 ATM, 1 BRCA1) showed evidence of biallelic inactivation. Conclusion: 5.9% of PC patients with predominantly sporadic disease have a pathogenic germline mutation in cancer predisposition genes associated with PC risk. However, carrier status did not significantly affect age at diagnosis, survival, personal or family history of malignancy in this cohort. Second hit mechanisms were identified in 12 (52.2%) cases, supporting a potential role in pancreatic tumorgenesis. An expanded analysis of the germline data is required to further understand the genetic basis of both sporadic and familial PC. Citation Format: Skye McKay, Jeremy Humphris, Amber Johns, Mark Pinese, Ann-Marie Patch, Katia Nones, Australian Pancreatic Cancer Genome Initiative (APGI), Sean Grimmond, Andrew Biankin, Nicola Waddell.{Authors}. Assessment of germline cancer predisposition genes in 392 unselected pancreatic cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A02.