Abstract 1572: Inherited truncating RAD52 variant discovered using integrated germline- somatic analysis predicts clinical outcome in patients with lung cancers
Authors: Mukherjee Semanti , Srinivasan Preethi , Bandlamudi Chaitanya , Hellmann Matthew D. , Ravichandran Vignesh , Selvan Myvizhi Esai , Kemel Yelena , Mandelker Diana , Zauderer Marjorie , Walsh Michael , Zehir Ahmet , Carlo Maria I , Cadoo Karen , Lipkin Steven M , Ladanyi Marc , Solit David , Robson Mark , Zhang Liying , Jones David , Rudin Charles , Klein Robert , Stadler Zsofia , Vijai Joseph , Gumus Zeynep , Taylor Barry , Berger Michael , Kenneth Kenneth 
Published: August 2019

Most of the heritability of lung cancer, estimated at 18% in population studies, remains unexplained. We employed a framework for variant interpretation utilizing integrated germline and somatic data.The lung cancer patients(pts) enrolled between 01/2014 and 05/2016 underwent sequencing analysis for 468 genes using MSK IMPACT with pathogenicity assessment performed using ACMG guidelines. Loss of heterozygosity (LOH) in tumor was inferred using the FACETS algorithm. A poorly characterized truncating variant was classified as “potential pathogenic variant” if we observed LOH of the relevant allele in the tumor and the gene was previously reported co-segregating in family studies or significant in genome wide association studies (GWAS). Frequencies of pathogenic germline variants were compared to population frequencies in the genome aggregation database (gnomAD).As per IRB protocol, germline results were anonymized for all cases. 2686 pts consented to tumor-normal sequencing of whom, 80% had lung adenocarcinoma, 10% squamous cell carcinoma and 5% small cell lung cancer diagnosis. We discovered a new truncating RAD52 p.Ser346Ter variant in 89 (3.3%) lung cancer patients; 47(53%) patients had LOH in tumor (23 pts with wild type allele loss and 24 patients with mutant allele loss). Previous lung cancer GWAS had reported common variants at the RAD52 locus as lung cancer susceptibility loci. The identified RAD52 truncating mutation may represent the functional variant within the risk haplotype. Clinico-pathological association with the RAD52 variant suggested that the mutation was more common in patients who had &lt;5 pack years of smoking history (5% in non-smokers versus 2.8% in smokers; OR=1.8, 95%CI=1-3.2,p-value=0.03), more commonly associated with EGFR oncogenic mutations (5.4% vs 2.8%; p-value=0.01) or MYC amplification (8.3% vs 3%; p=0.001) and had a poorer prognosis compared to patients without the variant (adjusted for smoking status; HR=1.5, 95%CI=1-2.4,p-value=0.04). We also identified 237 (8.8%) pts harboring pathogen germline variants in 28 cancer predisposition genes based on ACMG criteria, including 3 DNA repair genes significantly enriched in lung cancer cases compared to gnomAD controls; BRCA2 (OR=2, 95% CI= 1.3- 4.9), TP53 (OR=10.7, 95% CI=2.9-32.7)and NBN (OR= 9.6; 95% CI= 3-26.1) . Notably, 4/5 (80%) TP53variants and 9 /19 (47%) BRCA2 variants showed loss of heterozygosity (LOH) of the wild-type allele in tumor. In conclusion, we discovered a novel truncating RAD52 variant associated with clinical characteristics and poor prognosis, supporting the biological role of pathogenic mutations in DNA repair genes, including BRCA2, in the pathogenesis of a subset of hereditary lung tumors. These data warrant follow-up to refine the scope of germline genetic testing for lung cancer patients.

Citation Format: Semanti Mukherjee, Preethi Srinivasan, Chaitanya Bandlamudi, Matthew D. Hellmann, Vignesh Ravichandran, Myvizhi Esai Selvan, Yelena Kemel, Diana Mandelker, Marjorie Zauderer, Michael Walsh, Ahmet Zehir, Maria I Carlo, Karen Cadoo, Steven M Lipkin, Marc Ladanyi, David Solit, Mark Robson, Liying Zhang, David Jones, Charles Rudin, Robert Klein, Zsofia Stadler, Joseph Vijai, Zeynep Gumus, Barry Taylor, Michael Berger, Kenneth Kenneth. Inherited truncating RAD52 variant discovered using integrated germline- somatic analysis predicts clinical outcome in patients with lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1572.