Defective homologous recombination in human cancers

Cerbinskaite, Aiste; Mukhopadhyay, Asima; Plummer, Elizabeth Ruth; Curtin, Nicola J.; Edmondson, Richard J.

doi:10.1016/j.ctrv.2011.04.015

Cited by 63 publications

(43 citation statements)

References 220 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inactivation of both BRCA1 or BRCA2 is rarely seen together (7), suggesting that disruption of either gene is functionally equivalent or lethal in combination. Collectively, changes in BRCA1/2, together with germline or somatic mutation, methylation, or amplification of other members of the HRR pathway including EMSY, FANC-family genes, RAD51C, and PTEN occur in approximately 50% of HGSC, a figure that accords with functional assays of defective HRR in HGSC (10).…”

Section: Introductionmentioning

confidence: 80%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 80%

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

View full text Add to dashboard Cite

show abstract

“…192 Sporadic tumors may display 'BRCAness', that is, HR defects without mutations in BRCA1 or BRCA2. 171,193 BRCAness can be explained by epigenetic inactivation (for instance due to promoter methylation) of BRCA1 or BRCA2, (epi)mutations in other genes, post-translational protein modifications, as well as pharmaclogical inhibitors that inactivate HR-dependent repair:…”

Section: Box 2 Brcanessmentioning

confidence: 99%

Predictive biomarkers for cancer therapy with PARP inhibitors

Michels

Vitale²,

Saparbaev

et al. 2013

Oncogene

View full text Add to dashboard Cite

Poly(ADP-ribose) polymerase (PARP) inhibitors have raised high expectations for the treatment of multiple malignancies. PARP inhibitors, which can be used as monotherapies or in combination with DNA-damaging agents, are particularly efficient against tumors with defects in DNA repair mechanisms, in particular the homologous recombination pathway, for instance due to BRCA mutations. Thus, deficient DNA repair provides a framework for the success of PARP inhibitors in medical oncology. Here, we review encouraging results obtained in recent clinical trials investigating the safety and efficacy of PARP inhibitors as anticancer agents. We discuss emerging mechanisms of regulation of homologous recombination and how inhibition of DNA repair might be used in cancer therapy. We surmise that the identification of patients that are likely to benefit from PARP inhibition will improve the clinical use of PARP inhibitors in a defined target population. Thus, we will place special emphasis on biomarker discovery.

show abstract

“…The detailed analysis of EOC by TCGA network has revealed a homologous recombination defect (HRd) in approximately 50 % of HGSC cases [6]. HRd not only results from germ-line or somatic mutations or epigenetic silencing of BRCA1/2 genes but also from defects in various other genes such as EMSY, RAD51C, ATR, ATM, PTEN, and genes in Fanconi anemia (FA) pathway [7]. Compatible with the possible association between HR status and response to platinum therapy, BRCA1/2 mutation carriers respond better to platinum-based chemotherapy [8] and have an improved 5-year overall survival as compared to sporadic cases [9,10].…”

Section: Introductionmentioning

confidence: 99%

Assessment of PARP protein expression in epithelial ovarian cancer by ELISA pharmacodynamic assay and immunohistochemistry

et al. 2016

View full text Add to dashboard Cite

Targeting Poly (ADP-ribose) polymerase 1 (PARP-1) involved in base excision repair (BER) has been shown to be a clinically effective treatment strategy in epithelial ovarian cancer (EOC) defective in homologous recombination (HR). The aim of this study was to evaluate fresh EOC tumor tissue in regard to PAR (Poly (ADP-ribose)) concentration as a surrogate marker for PARP activity and PARP protein expression in archival samples by immunohistochemistry (IHC). The prospective study cohort consisted of 57 fresh tumor samples derived from patients undergoing primary (n = 38) or interval debulking surgery (n = 19) for EOC and parallel archival paraffin-embedded tumor samples. PARP activity in fresh frozen tumor tissue was assessed by an enzymatic chemiluminescence assay and PARP protein expression in paraffin-embedded tumor tissue by IHC. No correlation was detected between PARP enzyme activity and PARP staining by IHC (p = 0.82). High PARP activity was associated with platinum sensitivity both in the entire study cohort (p = 0.022) and in the high-grade subgroup (p = 0.017). High PARP activity was also associated with improved progression-free survival (PFS) (32 vs 14 months, log-rank p = 0.009). However, PARP immunostaining pattern was not predictive of patient survival. In conclusion, we present a novel finding of high PARP activity associated with platinum sensitivity and improved PFS in EOC. There was no association between PARP IHC and pharmacodynamic assay, and the correlation of PARP IHC with clinico-pathological characteristics and patient survival was poor. Pharmacodynamic assay rather than IHC seems to reflect better biologically significant PARP.

show abstract

Defective homologous recombination in human cancers

Cited by 63 publications

References 220 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

Predictive biomarkers for cancer therapy with PARP inhibitors

Assessment of PARP protein expression in epithelial ovarian cancer by ELISA pharmacodynamic assay and immunohistochemistry

Contact Info

Product

Resources

About