Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations.

نویسندگان

  • Joshy George
  • Kathryn Alsop
  • Dariush Etemadmoghadam
  • Heather Hondow
  • Thomas Mikeska
  • Alexander Dobrovic
  • Anna deFazio
  • Gordon K Smyth
  • Douglas A Levine
  • Gillian Mitchell
  • David D Bowtell
چکیده

PURPOSE High-grade serous carcinoma (HGSC) accounts for the majority of epithelial ovarian cancer deaths. Genomic and functional data suggest that approximately half of unselected HGSC have disruption of the BRCA pathway and defects in homologous recombination repair (HRR). Pathway disruption is regarded as imparting a BRCAness phenotype. We explored the molecular changes in HGSC arising in association with specific BRCA1/BRCA2 somatic or germline mutations and in those with BRCA1 DNA promoter methylation. EXPERIMENTAL DESIGN We describe gene expression and copy number analysis of two large cohorts of HGSC in which both germline and somatic inactivation of HRR has been measured. RESULTS BRCA1 disruptions were associated with the C2 (immunoreactive) molecular subtype of HGSC, characterized by intense intratumoral T-cell infiltration. We derived and validated a predictor of BRCA1 mutation or methylation status, but could not distinguish BRCA2 from wild-type tumors. DNA copy number analysis showed that cases with BRCA1 mutation were significantly associated with amplification both at 8q24 (frequencies: BRCA1 tumors 50%, BRCA2 tumors 32%, and wild-type tumors 9%) and regions of the X-chromosome specifically dysregulated in basal-like breast cancer (BLBC; BRCA1 62%, BRCA2 34%, and wild-type 35%). Tumors associated with BRCA1/BRCA2 mutations shared a negative association with amplification at 19p13 (BRCA1 0%, BRCA2 3%, and wild-type 20%) and 19q12 (BRCA1 6%, BRCA2 3%, and wild-type 29%). CONCLUSION The molecular differences between tumors associated with BRCA1 compared with BRCA2 mutations are in accord with emerging clinical and pathologic data and support a growing appreciation of the relationship between HGSC and BLBC.

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منابع مشابه

Human Cancer Biology Nonequivalent Gene Expression and Copy Number Alterations in High-Grade Serous Ovarian Cancers with BRCA1 and BRCA2 Mutations

Purpose: High-grade serous carcinoma (HGSC) accounts for the majority of epithelial ovarian cancer deaths. Genomic and functional data suggest that approximately half of unselected HGSC have disruption of the BRCA pathway and defects in homologous recombination repair (HRR). Pathway disruption is regarded as imparting a BRCAness phenotype. We explored the molecular changes in HGSC arising in as...

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Integrated genomic analyses of ovarian carcinoma

Acatalogue ofmolecular aberrations that cause ovarian cancer is critical for developing and deploying therapies thatwill improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumo...

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Integrated genomic analyses of ovarian carcinoma

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Integrated genomic analyses of ovarian carcinoma

Acatalogue ofmolecular aberrations that cause ovarian cancer is critical for developing and deploying therapies thatwill improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumo...

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عنوان ژورنال:
  • Clinical cancer research : an official journal of the American Association for Cancer Research

دوره 19 13  شماره 

صفحات  -

تاریخ انتشار 2013