MSH2 role in BRCA1-driven tumorigenesis: A preliminary study in yeast and in human tumors from BRCA1-VUS carriers

Maresca, Luisa; Spugnesi, Laura; Lodovichi, Samuele; Cozzani, Cristina; Naccarato, Antonio Giuseppe; Tancredi, Mariella; Collavoli, Anita; Falaschi, Elisabetta; Rossetti, Elena; Aretini, Paolo; Cervelli, Tiziana; Galli, Alvaro; Caligo, Maria A.

doi:10.1016/j.ejmg.2015.09.005

Cited by 17 publications

(29 citation statements)

References 38 publications

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“…Recent evidence suggests that MSH2 is able to modulate BRCA1 activity too. 21 It's likely that the ongoing cross-talk between these genes involved in the mechanism of DNA repair may sensitize cancer cells to improve or decrease the efficacy of different anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients

Omarini

Bettelli²,

Caprera³

et al. 2018

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients

Omarini

Bettelli²,

Caprera³

et al. 2018

Cancer Biology & Therapy

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“…As the expression of BRCA1 cancer-related variants increased HR in yeast, we previously proposed the “yeast recombination assay” as reliable method to determine the functional impact of VUS ( Caligo et al, 2009 ). Recently, we demonstrated in yeast that MSH2 affects BRCA1-induced HR and, in parallel, we found a high frequency (36%) of MSH2 somatic mutations in breast and ovarian tumors from BRCA1 missense variant carriers ( Maresca et al, 2015 ). Taking advantage of the functional and sequence homology between human and yeast DNA repair genes ( Sung et al, 2000 ; Liu et al, 2017 ), we determined whether the expression of several BRCA1 pathogenic and neutral variants in MSH6, RAD50, MRE11 , and RAD51 yeast deletion mutants affects HR.…”

Section: Introductionmentioning

confidence: 69%

Functional Interaction Between BRCA1 and DNA Repair in Yeast May Uncover a Role of RAD50, RAD51, MRE11A, and MSH6 Somatic Variants in Cancer Development

et al. 2018

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In this study, we determined if BRCA1 partners involved in DNA double-strand break (DSB) and mismatch repair (MMR) may contribute to breast and ovarian cancer development. Taking advantage the functional conservation of DNA repair pathways between yeast and human, we expressed several BRCA1 missense variants in DNA repair yeast mutants to identify functional interaction between BRCA1 and DNA repair in BRCA1-induced genome instability. The pathogenic p.C61G, pA1708E, p.M775R, and p.I1766S, and the neutral pS1512I BRCA1 variants increased intra-chromosomal recombination in the DNA-repair proficient strain RSY6. In the mre11, rad50, rad51, and msh6 deletion strains, the BRCA1 variants p.C61G, pA1708E, p.M775R, p.I1766S, and pS1215I did not increase intra-chromosomal recombination suggesting that a functional DNA repair pathway is necessary for BRCA1 variants to determine genome instability. The pathogenic p.C61G and p.I1766S and the neutral p.N132K, p.Y179C, and p.N550H variants induced a significant increase of reversion in the msh2Δ strain; the neutral p.Y179C and the pathogenic p.I1766S variant induced gene reversion also, in the msh6Δ strain. These results imply a functional interaction between MMR and BRCA1 in modulating genome instability. We also performed a somatic mutational screening of MSH6, RAD50, MRE11A, and RAD51 genes in tumor samples from 34 patients and identified eight pathogenic or predicted pathogenic rare missense variants: four in MSH6, one in RAD50, one in MRE11A, and two in RAD51. Although we found no correlation between BRCA1 status and these somatic DNA repair variants, this study suggests that somatic missense variants in DNA repair genes may contribute to breast and ovarian tumor development.

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“…HDAC1 and RBBP7 are among the blue nodes representing chromosome organization proteins. Another protein identified in this sub-network was a DNA mismatch repair protein which is a well-known marker for ovarian cancer, MSH2 (Maresca et al, 2015; Stewart et al, 2017; Xiao et al, 2014; Zhao et al, 2018). Additionally, subunits of the tumor suppressor complex SWI/SNF, including ARID1A, SMARCC1 and SMARCA2, were among the proteins in the enriched chromosome organization network.…”

Section: Resultsmentioning

confidence: 99%

Orthogonal proteomic platforms and their implications for the stable classification of high-grade serous ovarian cancer subtypes

Thomas

Friedrich

Schnaubelt

et al. 2019

Preprint

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SummaryThe National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) has established a two-dimensional liquid chromatography-tandem mass spectrometry (2DLC-MS/MS) workflow using isobaric tagging to compare protein abundance across samples. The workflow has been used for large-scale clinical proteomic studies with deep proteomic coverage within and outside of CPTAC. SWATH-MS, an instance of data-independent acquisition (DIA) proteomic methods, was recently developed as an alternate proteomic approach. In this study, we analyzed remaining aliquots of peptides using SWATH-MS from the original retrospective TCGA samples generated for the CPTAC ovarian cancer proteogenomic study (Zhang et al., 2016). The SWATH-MS results indicated that both methods confidently identified differentially expressed proteins in enriched pathways associated with the robust Mesenchymal subtype of high-grade serous ovarian cancer (HGSOC) and the homologous recombination deficient tumors also present in the original study. The results demonstrated that SWATH/DIA-MS presents a promising complementary or orthogonal alternative to the CPTAC harmonized proteomic method, with the advantages of simpler, faster, and cheaper workflows, as well as lower sample consumption. However, the SWATH/DIA-MS workflow resulted in shallower proteome coverage. Overall, we concluded that both analytical methods are suitable to characterize clinical samples such as in the high-grade serous ovarian cancer study, providing proteomic workflow alternatives for cancer researchers depending on the specific goals and context of the studies.

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MSH2 role in BRCA1-driven tumorigenesis: A preliminary study in yeast and in human tumors from BRCA1-VUS carriers

Cited by 17 publications

References 38 publications

Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients

Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients

Functional Interaction Between BRCA1 and DNA Repair in Yeast May Uncover a Role of RAD50, RAD51, MRE11A, and MSH6 Somatic Variants in Cancer Development

Orthogonal proteomic platforms and their implications for the stable classification of high-grade serous ovarian cancer subtypes

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