BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor
Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in and genes. Although promoter methylation is a we...
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Published in: | International journal of molecular sciences Vol. 21; no. 24; p. 9708 |
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Main Authors: | , , , , , , , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
Switzerland
MDPI AG
19-12-2020
MDPI |
Subjects: | |
Online Access: | Get full text |
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Summary: | Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in
and
genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about
gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without
germline mutations. We identified 20/88 (22.7%) EOCs showing
promoter methylation, including 17/88 (19.3%) in
and 4/86 (4.6%) in
promoters, one of which showing concomitant
methylation. Mean methylation levels were 49.6% and 45.8% for
and
respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive
methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of
genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline
-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with
methylation, even without
mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic
methylation of PARP-therapy response. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1422-0067 1661-6596 1422-0067 |
DOI: | 10.3390/ijms21249708 |