Abstract 5590: Molecular characterization of pancreatic tumors arising in the background of germline BRCA mutations

Abstract

Abstract Background: BRCA1 and BRCA2 are tumor suppressor genes which play a role in the repair of DNA double stranded breaks and the maintenance of genomic stability. Inherited BRCA mutations increase the risk of development of pancreatic cancer. In sporadic tumors BRCA mutations occur late in pancreatic tumorigenesis. Few studies to date have examined molecular heterogeneity within pancreatic tumors with respect to founder and progressor mutations. This is the first study to examine heterogeneity of mutations in pancreatic carcinomas associated with germline BRCA mutations. Design: Cases of pancreatic tumors arising in four patients with previously confirmed germline BRCA1 or BRCA2 mutations were identified from our case files. Representative sections of formalin-fixed, paraffin embedded tissue from surgical resection specimens were reviewed and 3 sections of tumor from different geographic regions and 1 section of non-tumor tissue were selected for molecular analysis for each case. Samples were manually macrodissected and genomic DNA was isolated. Genomic DNA was used for target capture and amplification of 212 amplicons targeting mutational hotspots in 48 genes using the TruSeq Amplicon Cancer Panel. Next generation sequencing was performed on the MiSeq Benchtop Sequencer and analyzed with NextGENe software. Results: In all cases concordant results were observed in all three tumor samples, with no evidence of intratumoral heterogeneity for the genes tested. In one patient with a BRCA1 germline mutation, TP53 and SMAD4 mutations were identified. In two patients with germline BRCA2 mutations, two additional driver mutations were identified involving KRAS, TP53, or SMAD4. In one case with BRCA2 germline mutation, no additional mutations were identified. Conclusion: Pancreatic tumors arising in the background of germline BRCA mutations had between 1-3 driver mutations per tumor, which is consistent with the reported numbers of driver mutations in sporadically arising pancreatic tumors. No mutual exclusivity among the mutated genes was observed. Mutations observed include KRAS codon 12 mutation, TP53 mutation (within the DNA binding domain), and SMAD4 mutation. Taken together, these results suggest that pancreatic tumors occurring in BRCA patients show similar mutational profiles of key oncogenes and tumor suppressor genes as seen in sporadic tumors with little heterogeneity with respect to these driver mutations. Citation Format: Susan Hsiao, Anne Koehne de Gonzalez, Mahesh M. Mansukhani, Robert L. Fine, Helen E. Remotti. Molecular characterization of pancreatic tumors arising in the background of germline BRCA mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5590. doi:10.1158/1538-7445.AM2014-5590