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

Abstract

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. 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. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors 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: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 hadmore » 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. 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.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
COLLABORATION - U. BritishColumbia
OSTI Identifier:
933109
Report Number(s):
LBNL-63765
R&D Project: 443180; BnR: KP1104010; TRN: US200814%%857
DOE Contract Number:  
DE-AC02-05CH11231
Resource Type:
Journal Article
Journal Name:
BMC Cancer
Additional Journal Information:
Journal Volume: 8; Journal Issue: 17; Related Information: Journal Publication Date: 01/22/2008
Country of Publication:
United States
Language:
English
Subject:
59; CARCINOMAS; GENES; GENETICS; METHYLATION; MUTATIONS; NEOPLASMS; PROMOTERS; SOMATIC MUTATIONS

Citation Formats

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, and Huntsman, David G. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities. United States: N. p., 2007. Web.
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. Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities. United States.
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, and Huntsman, David G. 2007. "Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities". United States. https://www.osti.gov/servlets/purl/933109.
@article{osti_933109,
title = {Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities},
author = {Press, Joshua Z and De Luca, Alessandro and Boyd, Niki and Young, Sean and Troussard, Armelle and Ridge, Yolanda and Kaurah, Pardeep and Kalloger, Steve E and Blood, Katherine A and Smith, Margaret and Spellman, Paul T and Wang, Yuker and Miller, Dianne M and Horsman, Doug and Faham, Malek and Gilks, C Blake and Gray, Joe and Huntsman, David G},
abstractNote = {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. 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. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors 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: tumors 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. 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.},
doi = {},
url = {https://www.osti.gov/biblio/933109}, journal = {BMC Cancer},
number = 17,
volume = 8,
place = {United States},
year = {Mon Jul 23 00:00:00 EDT 2007},
month = {Mon Jul 23 00:00:00 EDT 2007}
}