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Abstract
Introduction. Clinical data have shown that mutations in BRCA1/2 and other DNA repair genes confer a high sensitivity of ovarian tumors and certain other types of carcinomas to platinum or similar drugs. Analysis of BRCA1/2-negative ovarian cancers (OCs) that have shown a good response to platinum-based therapy appears to be a promising approach in the search for novel hereditary cancer genes.
Aim. To search for novel genetic OC determinants by analyzing clinical cases of successful primary treatment.
Materials and Methods. DNA samples from 123 patients with prolonged clinical remission were subjected to a three-stage analysis: 1) analysis of common pathogenic BRCA1/2 alleles; 2) targeted sequencing of other hereditary cancer genes (ATM, BLM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, NF2, PALB2, PMS2, POLD1, POLE, PTCH1, PTEN, RAD51C, RAD51D, RB1, TP53, TSC1, TSC2, WRN); 3) whole exome sequencing (WES).
Results. There were 41 (33 %) BRCA1/2 mutation carriers and seven patients carrying pathogenic variants in other hereditary cancer genes: ATM, BLM, NBN (n = 3), PALB2, and RAD51D.
Based on whole exome analysis, 12 genes with putative loss-of-function variants were selected: AEN, ATF5, BRIP1, CEBPA, FANCM, GREB1, GRWD1, P4HTM, POLA2, RAD50, RAD54B, STK36. Loss of heterozygosity at the corresponding gene locus was observed in the tumor tissue of carriers of inactivating variants in ATF5 and P4HTM. In the additional cohort of consecutive diagnostic OCs (n = 107), three more cases with putative inactivating variants in ATF5, BRIP1, and FANCM were identified.
Conclusion. Patients who exhibit a good response to platinum-based therapy represent a promising group for identifying hereditary OC susceptibility genes.
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