J Gynecol Oncol.  2017 Jul;28(4):e39. 10.3802/jgo.2017.28.e39.

Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing

• Zhao Q
• Yang J
• Li L
• Cao D
• Yu M
• Shen K
• the BGI Group

• KMID: 2413427
• DOI: http://doi.org/10.3802/jgo.2017.28.e39

Abstract

OBJECTIVE
To define genetic profiling of homologous recombination (HR) deficiency in Chinese ovarian cancer patients.
METHODS
we have applied next-generation sequencing to detect deleterious mutations through all exons in 31 core HR genes. Paired whole blood and frozen tumor samples from 50 Chinese women diagnosed with epithelial ovarian carcinomas were tested to identify both germline and somatic variants.
RESULTS
Deleterious germline HR-mutations were identified in 36% of the ovarian cancer patients. Another 5 patients had only somatic mutations. BRCA2 was most frequently mutated. Three out of the 5 somatic mutations were in RAD genes and a wider distribution of other HR genes was involved in non-serous carcinomas. BRCA1/2-mutation carriers had favorable platinum sensitivity (relative risk, 1.57, p<0.05), resulting in a 100% remission probability and survival rate. In contrast, mutations in other HR genes predicted poor prognosis. However, multivariate analysis demonstrated that platinum sensitivity and optimal cytoreduction were the independent impact factors influencing survival (hazards ratio, 0.053) and relapse (hazards ratio, 0.247), respectively.
CONCLUSION
our results suggest that a more comprehensive profiling of HR defect than merely BRCA1/2 could help elucidate tumor heterogeneity and lead to better stratification of ovarian cancer patients for individualized clinical management.

Keyword

BRCA 1; BRCA 2; Homologous Recombination; Next-generation Sequencing; Epithelial Ovarian Cancer

MeSH Terms

Adult
Aged
Antineoplastic Agents/therapeutic use
Ataxia Telangiectasia Mutated Proteins/genetics
Checkpoint Kinase 2/genetics
China
Cytoreduction Surgical Procedures
DNA Helicases/genetics
DNA Mutational Analysis/methods
DNA Repair Enzymes/genetics
DNA-Binding Proteins/genetics
Disease-Free Survival
Exome
Female
*Genes, BRCA1
*Genes, BRCA2
*Germ-Line Mutation
*Homologous Recombination
Humans
INDEL Mutation
Middle Aged
Neoplasm Recurrence, Local/*etiology
Neoplasm, Residual
Neoplasms, Glandular and Epithelial/*genetics/therapy
Nuclear Proteins/genetics
Ovarian Neoplasms/*genetics/therapy
Platinum Compounds/therapeutic use
Polymorphism, Single Nucleotide
Rad52 DNA Repair and Recombination Protein/genetics
Survival Rate
Antineoplastic Agents
DNA-Binding Proteins
Nuclear Proteins
Platinum Compounds
Rad52 DNA Repair and Recombination Protein
Checkpoint Kinase 2
Ataxia Telangiectasia Mutated Proteins
DNA Helicases
DNA Repair Enzymes