Highlights
- •Methylation and mutation of RAD51C or BRCA1 were mutually exclusive.
- •Methylation of BRCA1 was associated with younger age at diagnosis.
- •Germline BRCA1 mutations and BRCA1 methylation were associated with HGS histology.
Abstract
Objective
In ovarian carcinoma, mutations in homologous recombination DNA repair (HRR) genes,
including BRCA1 and RAD51C, are associated with increased survival and specific clinical features. Promoter
hypermethylation is another mechanism of reducing gene expression. We assessed whether
BRCA1 and RAD51C promoter hypermethylation is associated with similar survival and clinical characteristics.
Methods
Promoter methylation of BRCA1 and RAD51C was evaluated using methylation-sensitive PCR in 332 primary ovarian carcinomas.
Damaging germline and somatic mutations in 16 HRR genes were identified using BROCA
sequencing.
Results
BRCA1 methylation was detected in 22 carcinomas (6.6%) and RAD51C methylation in 9 carcinomas (2.7%). These small numbers limited the power to detect
differences in survival and platinum sensitivity. Mutations in one or more HRR genes
were found in 95 carcinomas (29%). Methylation of BRCA1 or RAD51C was mutually exclusive with mutations in these genes (P = 0.001). Patients whose carcinomas had BRCA1 methylation (57.7 years ± 2.5) or BRCA1 mutations (54.1 years ± 1.4) were younger than those without (63.3 years ± 0.8; P = 0.029, P < 0.0001). BRCA1 methylation and germline BRCA1 mutation were associated with high grade serous (HGS) histology (P = 0.045, P = 0.001). BRCA1 mutations were associated with increased sensitivity to platinum chemotherapy while
BRCA1 methylation was not (P = 0.034, P = 0.803). Unlike HRR mutations, methylation was not associated with improved overall
survival compared to cases without methylation or mutation.
Conclusions
Patients with BRCA1-methylated carcinomas share clinical characteristics with patients with BRCA1-mutated carcinomas including younger age and predominantly HGS histology. However,
unlike mutation, RAD51C and BRCA1 methylation were not associated with improved survival or greater sensitivity to
platinum chemotherapy.
Keywords
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Article info
Publication history
Published online: December 09, 2017
Accepted:
December 4,
2017
Received in revised form:
November 28,
2017
Received:
July 22,
2017
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
