title: MSH2 role in BRCA1-driven tumorigenesis: A preliminary study in yeast and in human tumors from BRCA1-VUS carriers.
abstract: BRCA1 interacts with several proteins implicated in homologous and non homologous recombination and in mismatch repair. The aim of this study is to determine if MSH2, a well known partner of BRCA1 involved in DNA repair, may contribute to breast and ovarian cancer development and progression. To better understand the functional interaction between BRCA1 and MSH2, we studied the effect of the deletion of MSH2 gene on BRCA1-induced genome instability in yeast. Preliminary results in yeast indicated that MSH2 and BRCA1 may interact to modulate homologous recombination (HR). We also carried out a genetic and epigenetic profiling of MSH2 gene by mutational analysis and promoter methylation evaluation in 9 breast and 2 ovarian tumors from carriers of BRCA1 unknown significance variants (VUS). 2/2 ovarian and 2/9 breast tumors carried MSH2 somatic mutations possible pathogenics (4/11, 36%): a missense mutation in exon 3 (p.G162R), a duplication of exon 1 and a deletion of exon 2. In addition, two germline synonymous variants in exon 11 were identified. None of the tumors showed promoter methylation. In conclusion, a surprisingly high frequency of MSH2 gene mutations has been found in tumor tissues from BRCA1 VUS carrier patients. This result supports the indication deriving from the yeast model that BRCA1 driven tumorigenesis may be modulated by MSH2.
authors.affiliation: Section of Genetic Oncology, University of Pisa, Pisa, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Maresca
authors.affiliation: Section of Genetic Oncology, University of Pisa, Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Spugnesi
authors.affiliation: Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Lodovichi
authors.affiliation: Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cozzani
authors.affiliation: Division of Surgical, Molecular, and Ultrastructural Pathology, University of Pisa, Pisa, Italy.
authors.forename: Antonio Giuseppe
authors.initials: AG
authors.lastname: Naccarato
authors.affiliation: Section of Genetic Oncology, University of Pisa, Pisa, Italy.
authors.forename: Mariella
authors.initials: M
authors.lastname: Tancredi
authors.affiliation: Section of Genetic Oncology, University of Pisa, Pisa, Italy.
authors.forename: Anita
authors.initials: A
authors.lastname: Collavoli
authors.affiliation: Section of Genetic Oncology, University of Pisa, Pisa, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Falaschi
authors.affiliation: Department of Senology, University of Pisa, Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Rossetti
authors.affiliation: Fondazione Pisana per la Scienza Onlus, Pisa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Aretini
authors.affiliation: Institute of Clinical Physiology, CNR, Pisa, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cervelli
authors.affiliation: Institute of Clinical Physiology, CNR, Pisa, Italy. Electronic address: alvaro.galli@ifc.cnr.it.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Galli
authors.affiliation: Section of Genetic Oncology, University of Pisa, Pisa, Italy. Electronic address: adelaide.caligo@do.unipi.it.
authors.forename: Maria Adelaide
authors.initials: MA
authors.lastname: Caligo
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D019175:DNA Methylation; D005091:Exons; D005260:Female; D059765:Homologous Recombination; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D059645:Mutation Rate; D011110:Polymorphism, Genetic; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: BRCA1; Hereditary breast and ovarian cancer; MSH2; Mutational analysis; Yeast functional assay