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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article number17
JournalBMC Cancer
Volume8
DOIs
StatePublished - Jan 22 2008
Externally publishedYes

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Epigenomics
Carcinoma
Mutation
Loss of Heterozygosity
Ovarian Neoplasms
Neoplasms
Gene Dosage
Germ-Line Mutation
Phosphatidylinositol 3-Kinases
Methylation
Immunohistochemistry
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Press, J. Z., De Luca, A., Boyd, N., Young, S., Troussard, A., Ridge, Y., ... Huntsman, D. G. (2008). Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer, 8, [17]. https://doi.org/10.1186/1471-2407-8-17

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; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

In: BMC Cancer, Vol. 8, 17, 22.01.2008.

Research output: Contribution to journalArticle

Press, JZ, De Luca, A, Boyd, N, Young, S, Troussard, A, Ridge, Y, Kaurah, P, Kalloger, SE, Blood, KA, Smith, M, Spellman, P, Wang, Y, Miller, DM, Horsman, D, Faham, M, Gilks, CB, Gray, J & Huntsman, DG 2008, 'Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities', BMC Cancer, vol. 8, 17. https://doi.org/10.1186/1471-2407-8-17
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 ; 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 have distinct molecular abnormalities. In: BMC Cancer. 2008 ; Vol. 8.
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title = "Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities",
abstract = "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.",
author = "Press, {Joshua Z.} and {De Luca}, Alessandro and Niki Boyd and Sean Young and Armelle Troussard and Yolanda Ridge and Pardeep Kaurah and Kalloger, {Steve E.} and Blood, {Katherine A.} and Margaret Smith and Paul Spellman and Yuker Wang and Miller, {Dianne M.} and Doug Horsman and Malek Faham and Gilks, {C. Blake} and Joe Gray and Huntsman, {David G.}",
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AU - Press, Joshua Z.

AU - De Luca, Alessandro

AU - Boyd, Niki

AU - Young, Sean

AU - Troussard, Armelle

AU - Ridge, Yolanda

AU - Kaurah, Pardeep

AU - Kalloger, Steve E.

AU - Blood, Katherine A.

AU - Smith, Margaret

AU - Spellman, Paul

AU - Wang, Yuker

AU - Miller, Dianne M.

AU - Horsman, Doug

AU - Faham, Malek

AU - Gilks, C. Blake

AU - Gray, Joe

AU - Huntsman, David G.

PY - 2008/1/22

Y1 - 2008/1/22

N2 - 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.

AB - 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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