Abstract Homologous recombination (HR) is important in DNA double-strand break repair. HR defects promote carcinogenesis and are associated with selective sensitivity to PARP-inhibitors and DNA-damaging agents. We collected 1029 tumor samples in 13 cancer types and used next-generation sequencing (NGS) to survey genes in the HR pathway. NGS on 591 genes was performed using formalin-fixed paraffin-embedded samples on the Illumina NextSeq platform (Caris Life Sciences, AZ). Mutations in as low as 5% of cells can be detected with > 99% confidence. Deletions larger than 27bp may not be detected by this method. Pathogenic or presumed pathogenic variants are counted as mutations. The table summarizes mutation rates of 7 key genes—ATM, BRCA1, BRCA2, CHEK1, CHEK2, PALB2 and PTEN—included in this pilot study. Another 17 HR genes—ATR, ATRX, BARD1, BLM, BRIP1, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11A, NBN, RAD50, RAD51, and RAD51B—were also analyzed. PTEN mutations were seen in 6.3% of tumors, ATM in 5%, BRCA1 in 2%, BRCA2 in 2%, PALB2 in 1%, and CHEK2 in 1%. No CHEK1 mutations were observed. Overall, 15% of tumors carry at least one mutation in any of the 7 key genes. The highest mutation rates were seen in endometrial (43%), glioblastoma (34%), and gastric cancers (23%). The highest rates of ATM (9.7%), BRCA2 (6.5%), and PALB2 (6.5%) were seen in gastric cancer, while the highest CHEK2 (5.6%), BRCA1 (7.3%) and PTEN (44%) mutations were seen in cholangiocarcinoma, ovarian and endometrial tumors, respectively. One 53-year old pt with metastatic poorly-differentiated gastric adenocarcinoma experienced ongoing radiographic partial response and dramatic symptom relief following 4 cycles of FOLFOX without surgery; tumor analysis revealed a nonsense PALB2 (S326*) gene mutation, while the other 23 HR genes were wild type. ERCC1 showed intact expression by IHC. Mutation rates of 7 genes on the HR pathway in 13 cancer typesEndometrialATMBRCA1BRCA2CHEK1CHEK2PALB2PTENAny of the 7 genesEndometrial (N = 35)00002.9%3.0%44.1%42.9%GBM (N = 47)2.1%2.1%000030.4%34.0%Gastric (N = 31)9.7%06.5%006.5%022.6%Bladder (N = 38)2.6%05.4%00010.8%18.4%Kidney (N = 41)2.5%0005.0%010.0%17.1%Ovarian (N = 82)3.7%7.3%1.2%01.2%01.3%14.6%Breast (N = 108)4.6%2.8%1.9%00.9%1.0%3.8%13.9%Cholangiocarcinoma (N = 36)2.8%02.8%05.6%02.9%13.9%CRC(N = 254)6.3%2.0%1.6%00.4%04.0%13.0%Pancreatic (N = 62)4.8%1.6%3.2%001.7%3.3%12.9%NSCLC(N = 234)6.5%00.9%001.4%2.6%11.1%Neuroendocrine(N = 35)2.9%000005.7%8.6%Esophageal (N = 26)3.8%000004.0%7.7%Overall(N = 1029)5.0%1.6%1.6%00.8%0.8%6.3%15.2% Thus, mutation rates of at least 8 to 43% in the HR pathway are reported from 13 cancer types. This method can potentially identify responders to DNA-damaging agents including platinum. Citation Format: Joanne Xiu, Ryan Bender, Brian Abbott, Zoran Gatalica, Sandeep Reddy, Mohamed Salem, Shelly Seward. Mutations on the homologous recombination pathway in 13 cancer types. [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 2750.