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Annals of Oncology Advance Access published online on July 22, 2008
Annals of Oncology, doi:10.1093/annonc/mdn409
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Methylation is less abundant in BRCA1-associated compared with sporadic breast cancer

K. P. M. Suijkerbuijk1, M. J. Fackler3, S. Sukumar3, C. H. van Gils4, T. van Laar1, E. van der Wall2, M. Vooijs1 and P. J. van Diest1,*

1 Department of Pathology
2 Division of Internal Medicine and Dermatology, University Medical Center Utrecht, The Netherlands
3 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore MD, USA
4 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands

* Corresponding to: Prof. P. J. van Diest, Department of Pathology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands. Tel: +31-88-7556565; Fax: +31-30-2544990; E-mail: p.j.vandiest{at}umcutrecht.nl

Background: Promoter methylation is a common epigenetic mechanism to silence tumor suppressor genes during breast cancer development. We investigated whether BRCA1-associated breast tumors show cancer-predictive methylation patterns similar to those found in sporadic tumors.

Patients and methods: Quantitative multiplex methylation-specific PCR of 11 genes involved in breast carcinogenesis (RARB, RASSF1, TWIST1, CCND2, ESR1, SCGB3A1, BRCA1, BRCA2, CDKN2A, APC, CDH1) was carried out on 32 BRCA1-associated and 46 sporadic breast carcinomas and on normal breast tissue from seven BRCA1 mutation carriers and 13 non-carriers.

Results: The extent of cumulative methylation increased with age (P < 0.001). The median cumulative methylation index (CMI) of all studied genes was significantly higher in tumors (89) than in normal tissue (13, P < 0.001). The median CMI was significantly lower in BRCA1-associated (59) than in sporadic breast tumors (122, P = 0.001), in estrogen receptor (ER)-negative tumors (73) than in ER-positive tumors (122, P = 0.005) and in lymph node-negative (77) compared with lymph node-positive tumors (137, P = 0.007). In subgroup analysis, the effect of a BRCA1 germline mutation on methylation proved to be independent of ER status, lymph node status and age.

Conclusions: These data indicate that BRCA1-associated breast cancers show less promoter methylation compared with sporadic breast carcinomas indicating a difference in disease etiology.

BRCA1, breast cancer, hereditary, methylation, QM-MSP

Received for publication April 14, 2008. Accepted for publication June 3, 2008.


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