Abstract A15: Exome sequencing identifies candidate tumor suppressor genes in familial pancreatic cancer.

Five to ten percent of pancreatic cancer (PC) clusters within families. Epidemiologic studies suggest that Familial Pancreas Cancer (FPC) is caused by highly penetrant germline mutations, but less than 20% of these genes have been identified. Characterizing the remaining genetic basis of FPC should improve outcomes through molecularly tailored prevention, screening and treatment protocols. Exome sequencing (ES) is a powerful new approach for detecting genetic causes of disease. However, the causal mutation is often indistinguishable from the hundreds of other rare nonsynonymous variants (RNV) detected by germline ES. In general, most familial cancer syndromes are caused by an inherited mutation that inactivates one allele of a tumor suppressor gene (TSG); the somatic inactivation of the second allele, i.e., loss of heterozygosity (LOH), initiates tumourigenesis. To increase the specificity of ES, we combined somatic and germline ES to identify candidate TSG (cTSG) in FPC with germline RNV and LOH. Patients with available snap frozen tumors were selected from the Ontario Pancreas Cancer Study. Histologic inspection of the snap frozen tumors determined their composition to be over 70% pancreatic ductal adenocarcinoma cells. DNA was extracted from snap frozen tumors and peripheral blood. Exomes were enriched using the Agilent ICGC or Illumina TruSeq kits, and sequenced with the Illumina Genome Analyzer IIx. Novoalign aligned sequencing reads, and SAMtools and Picard were used to process them further. The Genome Analysis Tool Kit detected variants. ANNOVAR and custom scripts annotated variants. We defined an RNV as: i) present in less than 0.1% of alleles in the 1000 Genomes Project March 2012 dataset, the NHLBI ESP5400 dataset, and dbSNP135; and ii) a missense, nonsense or splice site single-nucleotide variant, or an exonic indel. cTSG were defined as genes containing a germline heterozygous RNV and a second somatic intragenic RNV. Three FPC probands underwent somatic and germline ES. Over 90% of target bases were covered by at least 10 sequencing reads in all samples. FPC-1 was a 67-year-old male with PC whose maternal aunt and grandmother had PC. FPC-1 carried 1032 germline RNV and 11 somatic RNV. Only 2 somatic RNV were in genes with RNV in 24 PC sequenced by Jones et al. (Jones, Science, 2008). No KRAS or TP53 mutations were detected and no cTSG was identified. FPC-2 was a 55-year-old man with PC whose sister had PC at age 42 and mother also had PC. FPC2 carried 618 germline RNV and 18 somatic RNV. 5 of the somatic RNV were in genes mutated in Jones et al. This patient’s tumour has a KRAS and TP53 mutation. We identified a cTSG that may repress the mobilization of transposable elements. FPC-3 was a 20-yearold woman with PC whose maternal aunt had PC at 59. FPC-3 carried 418 germline RNV and 15 somatic RNV, 1 of which was in genes previously mutated in Jones et al. No mutations in KRAS or TP53 were detected. Here we identified a cTSG that is an ion channel strongly and selectively expressed in the pancreas. We are performing copy number analysis on blood and tumor samples to improve our sensitivity to detect LOH caused by large deletions. We are sequencing the coding region of the two cTSG we identified in 50 unrelated FPC probands to assess their contribution to FPC. These results will be ready for presentation at the AACR PC meeting. We have identified two cTSGs in FPC and characterized the somatic genetic landscape of three FPC, which seem to differ from sporadic PC. Recent studies suggest that FPC is genetically heterogeneous. Our new approach combining somatic and germline ES improves specificity, allowing the identification of causal germline mutations even when a gene is infrequently mutated in FPC. Citation Format: Robert C. Grant, Timothy Beck, Lakshmi Muthuswamy, Ayelet Borgida, Spring Holter, Stefano Serra, John McPherson, Steven Gallinger. Exome sequencing identifies candidate tumor suppressor genes in familial pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A15.

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