Absence of BRCA/FMR1 correlations in women with ovarian cancers

PLoS One. 2014 Jul 18;9(7):e102370. doi: 10.1371/journal.pone.0102370. eCollection 2014.

Abstract

Previously reported findings in Austrian BRCA1/2 mutation carriers suggested a possible dependency of embryos with BRCA1/2 mutations on so-called low alleles of the fragile X mental retardation 1 (FMR1) gene, characterized by less than 26 CGG repeats (CGG(n<26)). The hypothesis arose from a study reporting highly statistically significant enrichment of low FMR1 alleles, significantly exceeding low allele prevalence in a general population, suggesting embryo lethality of BRCA1/2 mutations, "rescued" by presence of low FMR1 alleles. Such a dependency would also offer an explanation for the so-called "BRCA-paradox," characterized by BRCA1/2 deficient embryonic tissues being anti-proliferative (thereby potentially causing embryo-lethality) but proliferative in malignant tumors, including breast and ovarian cancers. Follow up investigations by other investigators, however, at most demonstrated trends towards enrichment but, mostly, no enrichment at all, raising questions about the original observation and hypothesis. We in this study, therefore, investigated CGGn of the FMR1 gene of 86 anonymized DNA samples from women with various forms of ovarian cancer, and were unable to demonstrate differences in prevalence of low FMR1 alleles either between positive and negative ovarian cancer patients for BRCA1/2 or between ovarian cancer patients and reported rates in non-cancer populations. This raises further questions about a suggested dependency between BRCA1/2 and FMR1, but also raises the possibility that investigated Austrian BRCA1/2 carrier populations differ from those in other countries. Either only selected BRCA1/2 mutations, therefore, interact with low FMR1 alleles or the Austrian data reflect only coincidental observations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Case-Control Studies
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Humans
  • Mutation
  • Ovarian Neoplasms / genetics*

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • FMR1 protein, human
  • Fragile X Mental Retardation Protein

Grants and funding

This study was supported by funds from the not-for-profit Foundation for Reproductive Medicine (FRM), New York, N.Y. 10021, USA, and intramural funds from the Center for Human Reproduction (CHR) – New York, N.Y. 10021, USA, a for-profit fertility and research center. The FRM had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript, even though N.G. and D.H.B. are members of the foundation's Board. Since staff makes funding decisions at CHR, independent of CHR's ownership, funders at CHR had also no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. All of those responsibilities were exclusively the authors', among which N.G., CHR's owner, is one. The funders at CHR only provided support in form of salaries to N.G., V.A.K. and D.H.B. The specific roles of these authors are articulated in the author contribution section.