DNA repair capacity is impaired in healthy BRCA1 heterozygous mutation carriers

  • Vaclová T
  • Gómez-López G
  • Setién F
 et al. 
  • 26

    Readers

    Mendeley users who have this article in their library.
  • 15

    Citations

    Citations of this article.

Abstract

BRCA1 germline mutations increase the lifetime risk of developing breast and ovarian cancers. However, taking into account the differences in disease manifestation among mutation carriers, it is probable that different BRCA1 mutations have distinct haploinsufficiency effects and lead to the formation of different phenotypes. Using lymphoblastoid cell lines derived from heterozygous BRCA1 mutation carriers and non-carriers, we investigated the haploinsufficiency effects of various mutation types using qPCR, immunofluorescence, and microarray technology. Lymphoblastoid cell lines carrying a truncating mutation showed significantly lower BRCA1 mRNA and protein levels and higher levels of gamma-H2AX than control cells or those harboring a missense mutation, indicating greater spontaneous DNA damage. Cells carrying either BRCA1 mutation type showed impaired RAD51 foci formation, suggesting defective repair in mutated cells. Moreover, compared to controls, cell lines carrying missense mutations displayed a more distinct expression profile than cells with truncating mutations, which is consistent with different mutations giving rise to distinct phenotypes. Alterations in the immune response pathway in cells harboring missense mutations point to possible mechanisms of breast cancer initiation in carriers of these mutations. Our findings offer insight into how various heterozygous mutations in BRCA1 could lead to impairment of BRCA1 function and provide strong evidence of haploinsufficiency in BRCA1 mutation carriers.

Author-supplied keywords

  • BRCA1
  • Breast cancer
  • DNA repair
  • Gene expression profiling
  • Haploinsufficiency

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

  • Tereza Vaclová

  • Gonzalo Gómez-López

  • Fernando Setién

  • José María García Bueno

  • José Antonio Macías

  • Alicia Barroso

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free