Further Evidence for BRCA1 Communication with the Inactive X Chromosome

Silver, Daniel P.; Dimitrov, Stoil D.; Feunteun, Jean; Gelman, Rebecca; Drapkin, Ronny; Lu, Shihua D.; Shestakova, Elena; Velmurugan, Soundarapandian; DeNunzio, Nicholas J.; Dragomir, Serban; Mar, Jessica C.; Liu, Xiaoling; Rottenberg, Sven; Jonkers, Jos; Ganesan, Shridar; Livingston, David M.

doi:10.1016/j.cell.2007.02.025

Cited by 72 publications

(48 citation statements)

References 36 publications

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“…We also identified specific chromosomal aberrations and over expression of a subset of X chromosome genes in HGSC that were previously identified in BLBC (27), providing a further parallel between these tumor types and implying a common molecular relationship between specific X chromosome loci and BRCA1 (48)(49)(50).…”

Section: Time To Relapse (Mo) Time To Death (Mo)mentioning

confidence: 81%

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

George

Alsop

Etemadmoghadam

et al. 2013

Clinical Cancer Research

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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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Section: Time To Relapse (Mo) Time To Death (Mo)mentioning

confidence: 81%

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

George

Alsop

Etemadmoghadam

et al. 2013

Clinical Cancer Research

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“…Unfortunately, this does not shed light on how XIST deregulation or the loss of an inactive X chromosome confers a resistance phenotype. A link between BRCA1 and XIST has been investigated intensively (35)(36)(37)(38)(39). Furthermore, the deletion of Xist in mice leads to hematologic malignancies (40) and genomic instability of the X chromosome (41).…”

Section: Discussionmentioning

confidence: 99%

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

Schouten

Vollebergh

Opdam

et al. 2016

Molecular Cancer Therapeutics

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In previous studies, high expression of XIST and low expression of 53BP1 were respectively associated with poor systemic therapy outcome in patients and therapy resistance in BRCA1-deficient mouse tumor models, but have not been evaluated in BRCA1-deficient patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non-BRCA1-like identified patients enriched for defects in BRCA1 that benefit from high-dose (HD) alkylating chemotherapy compared with a conventional standard regimen. We investigated whether XIST and 53BP1 expression predicted poor outcome of HD chemotherapy within 28 BRCA1-like patients from a trial randomizing between HD [4 cycles 5-fluorouracil, epirubicin, cyclophosphamide (FEC) followed by 1 cycle HD carboplatin, thiotepa, cyclophosphamide] or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 statuses were available. High RNA expression of XIST (n ¼ 5) and low protein expression of 53BP1 (n ¼ 3) expression did not coincide. Patients with either one had poor outcome after treatment with HD chemotherapy, whereas patients with low expression of XIST and high expression of 53BP1 derived substantial benefit of this regimen on recurrence-free survival, disease-free survival, and overall survival, corroborating preclinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer. Mol Cancer Ther; 15(1); 190-8. Ó2015 AACR.

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“…Our approach assumes that there is a single X-linked locus responsible for the XCE effect and that there is a good XCE genotype/XIP phenotype correlation. Autosomal factors are likely involved in XCI, [16][17][18] however, as the mouse XCE is X-linked, 19 and most of the key elements involved in XCI of humans and mice are X-linked, we reasonably began our search for the human XCE on the X-chromosome. It may be that several loci interact to determine XIPs.…”

Section: Discussionmentioning

confidence: 99%

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

et al. 2011

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The gene dosage inequality between females with two X-chromosomes and males with one is compensated for by X-chromosome inactivation (XCI), which ensures the silencing of one X in every somatic cell of female mammals. XCI in humans results in a mosaic of two cell populations: those expressing the maternal X-chromosome and those expressing the paternal X-chromosome. We have previously shown that the degree of mosaicism (the X-inactivation pattern) in a Canadian family is directly related to disease severity in female carriers of the X-linked recessive bleeding disorder, haemophilia A. The distribution of X-inactivation patterns in this family was consistent with a genetic trait having a co-dominant mode of inheritance, suggesting that XCI choice may not be completely random. To identify genetic elements that could be responsible for biased XCI choice, a linkage analysis was undertaken using an approach tailored to accommodate the continuous nature of the X-inactivation pattern phenotype in the Canadian family. Several X-linked regions were identified, one of which overlaps with a region previously found to be linked to familial skewed XCI. SA2, a component of the cohesin complex is identified as a candidate gene that could participate in XCI through its association with CTCF.

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Further Evidence for BRCA1 Communication with the Inactive X Chromosome

Cited by 72 publications

References 36 publications

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

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

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

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