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abstract
online 14 September 2015
MSH2 role in BRCA1-driven tumorigenesis: A preliminary study in yeast and in human tumors from BRCA1-VUS carriers
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.
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