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BRCA1 methylation and BRCA1 mutations in ovarian cancer
Gynecologic Oncology 122 (2011) 459–463
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Letters to the Editor BRCA1 methylation and BRCA1 mutations in ovarian cancer To the Editor, With great interest we have read the much needed re-appraisal of BRCA1 methylation studies in ovarian cancer [1]. The authors noted that differences in experimental methods resulted in a broad range of BRCA1 methylation, between 5% and 40%. Indeed, Suijkerbuijk et al. [2] found a high discrepancy between methylation-specific PCR (MSP) and quantitative multiplex MSP (QM-MSP) in the same samples. However, two unrelated quantitative methods, QM-MSP and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), correlated strongly. We determined promoter methylation of BRCA1, 145–148 bp upstream from the transcription start site, with MS-MLPA in 50 sporadic and 25 BRCA1 germ line mutation-related ovarian cancers. None of the BRCA1-associated tumors compared with 14% of the sporadic tumors showed methylation of BRCA1 [3], consistent with the findings by others [4–7]. Only two cases of BRCA1-mutated breast cancer have been described in which methylation might have been a second hit [8,9]. Hence BRCA1 methylation appears to be incompatible with BRCA1 mutations. In our study, BRCA1 methylated ovarian tumors mimicked BRCA1 mutated tumors in that they were primarily grade 3 (86%) serous (86%) ovarian cancers. Furthermore, we found equal methylation of 23 other common tumor suppressor genes between BRCA1 mutated and BRCA1 methylated ovarian cancer. Therefore, BRCA1 methylated tumors could, likewise for BRCA1 mutated tumors, benefit from treatment with PARP inhibitors. As suggested by Senturk et al. [1], BRCA1 mutated ovarian cancers could benefit from PARP inhibitors in combination with demethylating agents. However, the synthetic lethality of PARP inhibitors could be abrogated by demethylating agents in BRCA1 methylated tumors. This stresses the importance of discerning BRCA1 mutation from BRCA1 methylation status, which seems mutually exclusive, for therapeutic decision making. Conflict of interest statement The authors declare that no conflict of interest exists.
[6] Press J, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, Kaurah P, Kalloger S, Blood K, Smith M, Spellman P, Wang Y, Miller D, Horsman D, Faham M, Gilks CB, Gray J, Huntsman D. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 2008;8:17. [7] Rathi A, Virmani AK, Schorge JO, Elias KJ, Maruyama R, Minna JD, Mok SC, Girard L, Fishman DA, Gazdar AF. Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. Clin Cancer Res 2002;8:3324–31. [8] Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedenfalk I, Godwin AK, Trojan J, Vaurs-Barrière C, Bignon Y-J, Ramus S, Benitez J, Caldes T, Akiyama Y, Yuasa Y, Launonen V, Canal MJ, Rodriguez R, Capella G, Peinado MA, Borg A, Aaltonen LA, Ponder BA, Baylin SB, Herman JG. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 2001;10:3001–7. [9] Tapia T, Smalley SV, Kohen P, Munoz A, Solis LM, Corvalan A, Faundez P, Devoto L, Camus M, Alvarez M, Carvallo P. Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors. Epigenetics 2008;3: 157–63.
Guus Martinus Bol Department of Pathology, University Medical Center Utrecht Cancer Center, PO Box 85500 3508 GA Utrecht, The Netherlands Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Traylor 217C, Baltimore, MD 21205, USA Paul Joannes van Diest Department of Pathology, University Medical Center Utrecht Cancer Center, PO Box 85500, 3508 GA Utrecht, The Netherlands Corresponding author. Fax: +31 30 2544990. E-mail address: [email protected].
doi:10.1016/j.ygyno.2010.11.047
Response to the Letter to the Editor by Bol and van Diest regarding the review article “BRCA1 methylation and BRCA1 mutations in ovarian cancer”
To the Editor:
References [1] Senturk E, Cohen S, Dottino PR, Martignetti JA. A critical re-appraisal of BRCA1 methylation studies in ovarian cancer. Gynecol Oncol 2010;119:376–83. [2] Suijkerbuijk KP, Pan X, van der Wall E, van Diest PJ, Vooijs M. Comparison of different promoter methylation assays in breast cancer. Anal Cell Pathol (Amst) 2010;33(3):131–41. [3] Bol GM, Suijkerbuijk KPM, Bart J, Vooijs M, Van Der Wall E, Van Diest PJ. Methylation profiles of hereditary and sporadic ovarian cancer. Histopathology 2010;57:363–70. [4] Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, Karlan BY. BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res 2000;60:5329–33. [5] Dworkin A, Spearman A, Tseng S, Sweet K, Toland A. Methylation not a frequent “second hit” in tumors with germline BRCA mutations. Familial Cancer 2009;8: 339–46.
We would like to thank Drs. Bol and van Diest for their interest in our recent review article, “BRCA1 methylation and BRCA1 mutations in ovarian cancer” [1]. More importantly, we appreciate their highlighting two recent publications from their group [2,3] which further supports the argument that the use of different technologies, along with analysis of upstream regions of differing sizes/different CpG islands, most likely underlies the differences in reported BRCA1 methylation frequencies. Moreover, they provide additional evidence that BRCA1 methylation and mutation appear to be mutually exclusive events yet can share similar clinical features. Indeed, nearly one decade ago, the first evidence was presented that on the
Contents lists available at ScienceDirect
Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y g y n o
Letters to the Editor BRCA1 methylation and BRCA1 mutations in ovarian cancer To the Editor, With great interest we have read the much needed re-appraisal of BRCA1 methylation studies in ovarian cancer [1]. The authors noted that differences in experimental methods resulted in a broad range of BRCA1 methylation, between 5% and 40%. Indeed, Suijkerbuijk et al. [2] found a high discrepancy between methylation-specific PCR (MSP) and quantitative multiplex MSP (QM-MSP) in the same samples. However, two unrelated quantitative methods, QM-MSP and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), correlated strongly. We determined promoter methylation of BRCA1, 145–148 bp upstream from the transcription start site, with MS-MLPA in 50 sporadic and 25 BRCA1 germ line mutation-related ovarian cancers. None of the BRCA1-associated tumors compared with 14% of the sporadic tumors showed methylation of BRCA1 [3], consistent with the findings by others [4–7]. Only two cases of BRCA1-mutated breast cancer have been described in which methylation might have been a second hit [8,9]. Hence BRCA1 methylation appears to be incompatible with BRCA1 mutations. In our study, BRCA1 methylated ovarian tumors mimicked BRCA1 mutated tumors in that they were primarily grade 3 (86%) serous (86%) ovarian cancers. Furthermore, we found equal methylation of 23 other common tumor suppressor genes between BRCA1 mutated and BRCA1 methylated ovarian cancer. Therefore, BRCA1 methylated tumors could, likewise for BRCA1 mutated tumors, benefit from treatment with PARP inhibitors. As suggested by Senturk et al. [1], BRCA1 mutated ovarian cancers could benefit from PARP inhibitors in combination with demethylating agents. However, the synthetic lethality of PARP inhibitors could be abrogated by demethylating agents in BRCA1 methylated tumors. This stresses the importance of discerning BRCA1 mutation from BRCA1 methylation status, which seems mutually exclusive, for therapeutic decision making. Conflict of interest statement The authors declare that no conflict of interest exists.
[6] Press J, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, Kaurah P, Kalloger S, Blood K, Smith M, Spellman P, Wang Y, Miller D, Horsman D, Faham M, Gilks CB, Gray J, Huntsman D. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer 2008;8:17. [7] Rathi A, Virmani AK, Schorge JO, Elias KJ, Maruyama R, Minna JD, Mok SC, Girard L, Fishman DA, Gazdar AF. Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. Clin Cancer Res 2002;8:3324–31. [8] Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedenfalk I, Godwin AK, Trojan J, Vaurs-Barrière C, Bignon Y-J, Ramus S, Benitez J, Caldes T, Akiyama Y, Yuasa Y, Launonen V, Canal MJ, Rodriguez R, Capella G, Peinado MA, Borg A, Aaltonen LA, Ponder BA, Baylin SB, Herman JG. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 2001;10:3001–7. [9] Tapia T, Smalley SV, Kohen P, Munoz A, Solis LM, Corvalan A, Faundez P, Devoto L, Camus M, Alvarez M, Carvallo P. Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors. Epigenetics 2008;3: 157–63.
Guus Martinus Bol Department of Pathology, University Medical Center Utrecht Cancer Center, PO Box 85500 3508 GA Utrecht, The Netherlands Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Traylor 217C, Baltimore, MD 21205, USA Paul Joannes van Diest Department of Pathology, University Medical Center Utrecht Cancer Center, PO Box 85500, 3508 GA Utrecht, The Netherlands Corresponding author. Fax: +31 30 2544990. E-mail address: [email protected].
doi:10.1016/j.ygyno.2010.11.047
Response to the Letter to the Editor by Bol and van Diest regarding the review article “BRCA1 methylation and BRCA1 mutations in ovarian cancer”
To the Editor:
References [1] Senturk E, Cohen S, Dottino PR, Martignetti JA. A critical re-appraisal of BRCA1 methylation studies in ovarian cancer. Gynecol Oncol 2010;119:376–83. [2] Suijkerbuijk KP, Pan X, van der Wall E, van Diest PJ, Vooijs M. Comparison of different promoter methylation assays in breast cancer. Anal Cell Pathol (Amst) 2010;33(3):131–41. [3] Bol GM, Suijkerbuijk KPM, Bart J, Vooijs M, Van Der Wall E, Van Diest PJ. Methylation profiles of hereditary and sporadic ovarian cancer. Histopathology 2010;57:363–70. [4] Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, Karlan BY. BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res 2000;60:5329–33. [5] Dworkin A, Spearman A, Tseng S, Sweet K, Toland A. Methylation not a frequent “second hit” in tumors with germline BRCA mutations. Familial Cancer 2009;8: 339–46.
We would like to thank Drs. Bol and van Diest for their interest in our recent review article, “BRCA1 methylation and BRCA1 mutations in ovarian cancer” [1]. More importantly, we appreciate their highlighting two recent publications from their group [2,3] which further supports the argument that the use of different technologies, along with analysis of upstream regions of differing sizes/different CpG islands, most likely underlies the differences in reported BRCA1 methylation frequencies. Moreover, they provide additional evidence that BRCA1 methylation and mutation appear to be mutually exclusive events yet can share similar clinical features. Indeed, nearly one decade ago, the first evidence was presented that on the