Nandakumar, Kannabiran

Abstract The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well-defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12-month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first-degree relative with PDAC, and 10 mutations were found in patients with first- or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancers. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of patients with pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 25(1); 207–11. ©2015 AACR.

Abstract Background: Specific germline alterations within the TERT, EGFR, CCDC26, CDKN2A/B, PHLDB1, TP53 and RTEL1 regions are associated with development of glioma. While some of these germline variants are associated with all gliomas (e.g. rs2736100 in TERT), others are associated with a specific morphologic and/or molecular subtype. For example, the RTEL1 region variants are associated with primary glioblastoma and rs55705857 in CCDC26 is associated with 1p/19q co-deleted oligodendrogliomas and with IDH mutant astrocytic gliomas. We hypothesized that germline variants in these regions will be associated with other molecular subtypes. The Cancer Genome Atlas (TCGA) and other groups have described molecular subtypes of glioma based on acquired somatic mutation patterns. Herein, we grouped glioma patients into mutation-based molecular subgroups based on three molecular alterations and determined if germline polymorphisms are associated with these mutation-based molecular subtypes. Methods: Five molecular subtypes were defined based on combinations of the following molecular alterations: TERT promoter mutation (TERTmut vs. TERTwt), IDH1/2 mutation (IDH mut vs. IDH wt) and 1p/19q co-deletion (1p19qcodel vs. 1p19q noncodel). Germline single nucleotide polymorphisms (SNPs) were evaluated by custom Illumina array analysis of blood-derived DNA and 1K genome imputation. Results: One hundred ninety-nine gliomas (24 oligodendrogliomas, 59 mixed oligoastrocytomas, 41 grade 2-3 astrocytomas and 75 glioblastomas) had both SNP data and mutation data available in order to assign them into the five molecular subgroups. The prevalence of each of the molecular subtypes was as follows: TERTmut/IDHmut/1p19qcodel (20%), TERTmut/IDHmut/1p19qnoncodel (5%), TERTmut/IDHwt/1p19qnoncodel (32%), TERTwt/IDHmut/1p19qnondel (35%) and TERTwt/IDHwt/1p19qnoncodel (8%). The TERT SNP (rs2736100) was protective for TERTmut/IDHmut/1p19qnoncodel and TERTwt/IDHmut/1p19qnoncodel gliomas. The CCDC26 SNP (rs55705857) was strongly associated with the risk of developing TERTmut/IDHmut/1p19qcodel and TERTwt/IDHmut/1p19qnoncodel gliomas. The TP53 SNP (rs7837822) was strongly associated with risk of developing TERTmut/IDHmut/1p19qnoncodel and TERTwt/IDHmut/1p19qnoncodel gliomas. Interestingly, while one RTEL1 region SNP (rs6062297) was strongly associated with glioma risk, RTEL1 SNPs rs6010620 and rs2297440 were protective for the development of TERTmut/IDHwt/1p19qnoncodel gliomas. We are currently in the process of validating these results using the TCGA glioblastoma and low grade glioma data. Conclusions: Glioma patients can be meaningfully classified according to their acquired mutation subtype. Importantly, our results suggest that there are significant associations between germline polymorphisms and mutation-based glioma molecular subtypes. Citation Format: Jeanette E. Eckel-Passow, Thomas M. Kollmeyer, Gobinda Sarkar, Anisha Chada, Paul A. Decker, Matthew L. Kosel, Alissa A. Caron, Hugues Sicotte, Kannabiran Nandakumar, Naresh Prodduturi, Brian P. O'Neill, Daniel H. Lachance, Robert B. Jenkins. The association of glioma germline risk SNPs with mutation-based molecular subgroups. [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 4714. doi:10.1158/1538-7445.AM2014-4714