Moore, Raymond M.

Objective: Bringing together genomics, transcriptomics, proteomics, and other –omics technologies is an important step towards developing highly personalized medicine. However, instrumentation has advances far beyond expectations and now we are able to generate data faster than it can be interpreted. Materials and Methods: We have developed PANDA ( P athway AND A nnotation) Explorer, a visualization tool that integrates gene-level annotation in the context of biological pathways to help interpret complex data from disparate sources. PANDA is a web-based application that displays data in the context of well-studied pathways like KEGG, BioCarta, and PharmGKB. PANDA represents data/annotations as icons in the graph while maintaining the other data elements (i.e. other columns for the table of annotations). Custom pathways from underrepresented diseases can be imported when existing data sources are inadequate. PANDA also allows sharing annotations among collaborators. Results : In our first use case, we show how easy it is to view supplemental data from a manuscript in the context of a user’s own data. Another use-case is provided describing how PANDA was leveraged to design a treatment strategy from the somatic variants found in the tumor of a patient with metastatic sarcomatoid renal cell carcinoma. Conclusion : PANDA facilitates the interpretation of gene-centric annotations by visually integrating this information with context of biological pathways. The application can be downloaded or used directly from our website http://bioinformaticstools.mayo.edu/research/panda-viewer/.

Abstract A better understanding of gene-specific risks for development of breast cancer will lead to improved screening, prevention, and therapeutic strategies for individuals identified to carry germline mutations. We performed targeted massively-parallel sequencing to identify mutations and large genomic rearrangements in 26 known or proposed breast cancer susceptibility genes in 2134 BRCA-negative women with familial breast cancer (FBC). A case-control analysis was performed comparing the frequency of internally classified mutations identified in FBC cases to that in non-Finnish European controls from the Exome Aggregation Consortium (ExAC) excluding samples from The Cancer Genome Atlas. Including large genomic rearrangements, mutations were identified in 8.2% of FBC cases compared to 6.2% of ExAC controls, including mutations in high-penetrance genes (0.6% in cases vs. 0.1% in controls), moderate-penetrance genes (3.7% vs 1.7%), and seven cases with two mutations (0.3%). The remainder of FBC cases and ExAC controls had mutations in proposed breast cancer genes (1.6% of cases vs 2.4% of controls), Lynch syndrome genes (0.5% vs. 0.5%) or were heterozygous MUTYH carriers (1.5% vs. 1.5%). Case-control analysis demonstrated significant associations with FBC for ATM, PALB2, and TP53 mutations (OR>3.0, p<10-4), BARD1 mutations (OR=3.2, p=0.012), and CHEK2 truncating mutations (OR=1.6, p=0.041). Our results therefore demonstrate that only approximately 4% of BRCA1/2 negative FBC patients have mutations in genes definitively associated with breast cancer at this time. Large case-control studies are needed to fully evaluate the breast cancer risks associated with moderate penetrance and proposed breast cancer susceptibility genes. Citation Format: Kara N. Maxwell, Thomas Paul Slavin, Jenna M. Lilyquist, Joseph Vijai, Susan L. Neuhausen, Steven N. Hart, Vignesh Ravichandran, Tinu Thomas, Ann Maria, Kasmintan A. Schrader, Raymond Moore, Chunling Hu, Brad Wubbenhorst, Brandon M. Wenz, Kurt D'Andrea, Susan M. Domchek, Mark E. Robson, Paulo Peterlongo, Paolo Radice, James M. Ford, Judy E. Garber, Csilla Szabo, Kenneth Offit, Katherine L. Nathanson, Fergus J. Couch, Jeffrey N. Weitzel. Risks of familial breast cancer associated with known and proposed breast cancer susceptibility genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2017-4265

Abstract Germline pathogenic variants in BRCA1 and BRCA2 account for 10% of ovarian cancer (OC), including ovarian, fallopian tube, and primary peritoneal carcinomas. Pathogenic variants in BRIP1, RAD51C, RAD51D, and other cancer predisposition genes have been observed in another 2% to 5% of OCs. However, the specific genes associated with OC and estimates of risk associated with pathogenic variants in the individual genes are not well defined. We sought to determine the relevance of multigene panel testing results for OC cases. The study was focused on 140,449 individuals, including 10,233 OC cases, receiving clinical panel testing of cancer predisposition genes. Standardized relative risks (SRR) for pathogenic variants in 18 cancer predisposition genes were estimated using reference controls from the Exome Aggregation Consortium (ExAC). The median (range) age at diagnosis of OC was 57 (21-90) years. OC cases were 76.2% Caucasian, 3.6% African American, 4.6% Asian, 4.7% Hispanic, and 10.9% unknown/other. Among the 10,233 OC cases, 1391 (13.6%) had pathogenic mutations, including 1032 pathogenic mutations among the 7793 Caucasian OC cases (13.2%). Using the non-Finnish European ExAC (excluding TCGA samples) reference controls, the allele frequency for all pathogenic variants in each gene was summed and compared to the frequency of mutations in the Caucasian OC cases. Pathogenic variants in the known OC predisposition genes: BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, and RAD51D were associated with a high risk of OC (SRR>4.0). Additionally, significant associations were observed for pathogenic variants in suspected OC risk genes ATM and PALB2 (SRR=2.06 and 2.78, respectively). This study identified several genes routinely screened on multigene panel testing that confer high or moderate risks of OC. Associations with known OC predisposition genes were confirmed. In addition, this study provides evidence that PALB2 is a moderate risk OC gene, and that ATM may confer lower to moderate risks of OC. If confirmed in future studies, these risks should be carefully considered in future screening and management of OC patients. In contrast, BARD1 and genes in the MRN complex were not associated with clinically relevant risks of OC. Citation Format: Jenna Lilyquist, Holly LaDuca, Eric Polley, Hermela Shimelis, Chunling Hu, Raymond Moore, Steven N. Hart, Fergus J. Couch, Jill Dolinsky, David E. Goldgar. Multigene panel testing and risk estimates in 10,233 ovarian cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1287. doi:10.1158/1538-7445.AM2017-1287

Abstract Breast cancer is the most common type of cancer, and has a strong heritable component, with approximately 15 percent of new cases having family history of breast cancer. Genetic panel testing for patients with a family history of breast cancer has become a popular clinical resource. However, the risk of breast cancer associated with inactivating mutations in the predisposition genes is largely undefined, creating critical limitations in the interpretations of the results from panel testing and subsequent medical management. The Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS) consortium was established to determine the risk of cancers associated with truncating mutations in the known predisposition genes and to extend these studies to the clinical classification of variants of uncertain significance (VUS) in the relevant genes. CARRIERS involves screening of approximately 30,000 population-based breast cancer cases and 30,000 study matched controls for mutations in 28 established or proposed breast cancer predisposition genes. Population-based risks for breast cancer associated with mutations in each gene will be estimated. In parallel, 10,000 breast cancer cases from moderate and high-risk breast cancer families will be similarly screened for mutations and the penetrance of the mutations in high-risk families will be estimated. Furthermore, VUS identified by mutation screening will be characterized by functional and family-based studies and models for classification of the clinical relevance of VUS in each gene will be developed. These data are expected to lead to improvements in cancer risk assessment and improved management of patients found to carry mutations or VUS in breast cancer predisposition. Citation Format: Jenna Lilyquist, Peter Kraft, Steven N. Hart, Emily J. Hallberg, Chunling Hu, Raymond Moore, Rohan Gnanaolivu, Susan M. Domchek, Jeffrey N. Weitzel, Katherine L. Nathanson, David E. Goldgar, Fergus J. Couch. The CARRIERS consortium: Establishing refined breast cancer risk estimates in known predisposition genes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 810.