Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

doi:10.1186/1471-2407-8-17

Title: Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

Journal Article · Tue Jan 22 00:00:00 EST 2008 · BMC Cancer

DOI:https://doi.org/10.1186/1471-2407-8-17· OSTI ID:1626528

Press, Joshua Z. ^[1]; De Luca, Alessandro ^[2]; Boyd, Niki ^[2]; Young, Sean ^[3]; Troussard, Armelle ^[2]; Ridge, Yolanda ^[4]; Kaurah, Pardeep ^[4]; Kalloger, Steve E. ^[5]; Blood, Katherine A. ^[4]; Smith, Margaret ^[6]; Spellman, Paul T. ^[7]; Wang, Yuker ^[8]; Miller, Dianne M. ^[9]; Horsman, Doug ^[10]; Faham, Malek ^[8]; Gilks, C. Blake ^[11]; Gray, Joe ^[12]; Huntsman, David G. ^[13]

Univ. of British Columbia, Vancouver, BC (Canada). Dept. of Obstetrics and Gynecology
Univ. of British Columbia, Vancouver, BC (Canada). Dept. of Pathology and Lab. Medicine
Univ. of British Columbia, Vancouver, BC (Canada). Dept. of Pathology and Lab. Medicine; British Columbia Cancer Agency, Vancouver, BC (Canada). Hereditary Cancer Program
British Columbia Cancer Agency, Vancouver, BC (Canada). Hereditary Cancer Program
Vancouver General Hospital, Vancouver, BC (Canada). Genetic Pathology Evaluation Centre of the Prostate Centre
The Royal Melbourne Hospital, Parkville (Australia). Moelcular Genetics
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Divsion
Affymetrix Inc., San Francisco, CA (United States)
Univ. of British Columbia, Vancouver, BC (Canada). Dept. of Gynecologic Oncology
Univ. of British Columbia, Vancouver, BC (Canada). Dept. of Pathology and Lab. Medicine; The Royal Melbourne Hospital, Parkville (Australia). Molecular Genetics
Univ. of British Columbia, Vancouver, BC (Canada). Dept. of Pathology and Lab. Medicine; Vancouver General Hospital, Vancouver, CA (Canada). Genetic Pathology Evaluation Centre fo the Prostate Centre
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division
Univ. of British Columbia, Vancouver, BC (Canada). Dept. of Pathology and Lab. Medicine; British Columbia Cancer Agency, Vancouver, BC (Canada). Hereditary Cancer Program; Vancouver General Hospital, Vancouver, CA (Canada). Genetic Pathology Evaluation Centre fo the Prostate Centre

Background: Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/ 2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. Methods: A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Results: Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. Conclusion: High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

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Research Organization:: Univ. of California, Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Cancer Institute of Canada; Michael Smith Foundation for Health Research; National Institutes of Health (NIH)

Grant/Contract Number:: AC03-76SF00098; 017051; INRUA006045; P50 CA83639; CA 58207; CA 64602

OSTI ID:: 1626528

Journal Information:: BMC Cancer, Vol. 8, Issue 1; ISSN 1471-2407

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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