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Article

BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor

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SC Anatomia Patologica, Ospedale di Circolo, ASST Settelaghi, 21100 Varese, Italy
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Centro di Ricerca dei Tumori Eredo-Familiari, Dipartimento di Medicina e Chirurgia, University of Insubria, 21100 Varese, Italy
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Dipartimento di Ostetricia e Ginecologia, ASST Settelaghi, University of Insubria, 21100 Varese, Italy
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Dipartimento di Medicina e Chirurgia, University of Insubria, 21100 Varese, Italy
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Programma di Genomica Medica, AOU SS Giovanni di Dio e Ruggi d’Aragona Università di Salerno, 84131 Salerno, Italy
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Laboratorio di Medicina Molecolare e Genomica Dipartimento di Medicina, Chirurgia e Odontoiatria “Scuola Medica Salernitana” Università di Salerno, Baronissi, 84084 Salerno, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(24), 9708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249708
Received: 17 November 2020 / Revised: 16 December 2020 / Accepted: 17 December 2020 / Published: 19 December 2020
(This article belongs to the Special Issue Molecular Advances in Cancer Genetics)
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 BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response. View Full-Text
Keywords: promoter methylation; BRCA genes; PARP inhibitors; ovarian cancer; pyrosequencing promoter methylation; BRCA genes; PARP inhibitors; ovarian cancer; pyrosequencing
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MDPI and ACS Style

Sahnane, N.; Carnevali, I.; Formenti, G.; Casarin, J.; Facchi, S.; Bombelli, R.; Di Lauro, E.; Memoli, D.; Salvati, A.; Rizzo, F.; Sessa, F.; Tibiletti, M.G. BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor. Int. J. Mol. Sci. 2020, 21, 9708. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249708

AMA Style

Sahnane N, Carnevali I, Formenti G, Casarin J, Facchi S, Bombelli R, Di Lauro E, Memoli D, Salvati A, Rizzo F, Sessa F, Tibiletti MG. BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor. International Journal of Molecular Sciences. 2020; 21(24):9708. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249708

Chicago/Turabian Style

Sahnane, Nora, Ileana Carnevali, Giorgio Formenti, Jvan Casarin, Sofia Facchi, Raffaella Bombelli, Eleonora Di Lauro, Domenico Memoli, Annamaria Salvati, Francesca Rizzo, Fausto Sessa, and Maria G. Tibiletti 2020. "BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor" International Journal of Molecular Sciences 21, no. 24: 9708. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249708

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