Abstract 2779: Assessing germline and somatic alterations in DNA repair pathway in cancer
Authors: Basu Gargi D. , White Tracey , LoBello Janine , Kurdoglu Ahmet , Trent Jeffrey , Peng Sen , Halbert Matthew , Royce Thomas 
Published: July 2017

Abstract
Introduction: DNA repair genes are involved with repair of single strand breaks as well as double strand breaks which ultimately maintain the genome integrity. The genes involved with DNA repair are frequently deregulated in cancer and these defects can be exploited therapeutically. Our study aims to explore somatic and germline changes in DNA repair genes across multiple cancer types.
Methods: Genomic profiling was performed on 226 tumor samples from 24 cancer types with ages ranging 19-82 years. We performed targeted exome sequencing of 562 genes in tumor and paired normal DNA which included 112 genes associated with cancer predisposition syndromes. In addition to identifying genomic changes in 33 key DNA repair genes (ATM, ATR, ARID1A, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, ERCC2, ERCC3, ERCC4, FANCA gene family, MMR genes, NBS1, PALB2, PTEN, RAD50, RAD51, TP53 and POLE), we also characterized germline mutations using public databases (ClinVar, Ensembl).
Results: Profiled specimens included breast cancer (17.5%), ovarian cancer (15%), CRC (11%), NSCLC (10%), uterine (6%), sarcoma (6%) and other cancers. The most commonly deleted or mutated (somatic) DNA repair genes included TP53 (55%), PTEN (16%), ARID1A (13%), FANCA (11%), ERCC2 (10%), and ATM, BAP1, CDK12, CHEK2 at 6% each and BRCA1/2 combined at (9%). Deleterious mutations in MMR genes were noted in 3.5% (8/226) which included 1 case of germline PMS2-S46I mutation. Interestingly, a 55 yr old male African American CRC patient harbored germline XPC-P334H mutation along with somatic MLH1-Y548fs. No mutations were found in FANCC, FANCF, FANCG and RAD51. Germline analysis revealed a total of 47 pathogenic and presumed pathogenic variants out of which 61.7%(29/47) were DNA repair genes. A total of 13% (30/226) of cases harbored germline variants in DNA repair genes. Germline events included 9 cases with BRCA1 and BRCA2 clinically significant mutations. Presence of loss of heterozygosity (LOH) at the BRCA locus in 5/9 cases and somatic mutations in 3/9 cases were noted in germline BRCA mutated samples. Germline and somatic BRCA1 and BRCA2 alterations were present in 10% (22/226) of total cohort and as expected, the majority were present in breast and epithelial ovarian cancer. Genetic deficiencies in DNA repair pathway genes are being exploited therapeutically with PARP inhibitors as well as DNA damaging chemotherapeutics.
Conclusions: Exome sequencing identified subsets of patients with loss of function events in DNA repair genes that may be associated with benefit from PARP inhibitors and platinum agents. Somatic and germline biomarker testing revealed occurrence of BRCA1/2 as well as other DNA repair gene alterations across multiple cancers. It is imperative to explore the DNA repair pathway beyond BRCA1 and BRCA2 in patient selection for PARP inhibitors and DNA damaging agents and further investigation of this pathway is warranted in ongoing clinical trials.
Citation Format: Gargi D. Basu, Tracey White, Janine LoBello, Ahmet Kurdoglu, Jeffrey Trent, Sen Peng, Matthew Halbert, Thomas Royce. Assessing germline and somatic alterations in DNA repair pathway in cancer [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 2779. doi:10.1158/1538-7445.AM2017-2779