Absence of BRCA/FMR1 Correlations in Women with Ovarian Cancers

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 (CGGn<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.

Circular RNA and mRNA profiling reveal competing endogenous RNA networks during avian leukosis virus, subgroup J-induced tumorigenesis in chickens

“…The DOCK4 functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells and in cell migration, could suppresses tumor invasion in osteosarcoma mouse cell lines [ 34 – 36 ]. FMR1 may be involved in the regulation of ATR-dependent signaling pathways such as BRCA1 phosphorylations and interact with BRCA in human Ovarian Cancers [ 37 ]. ZFHX3 may function as transcriptional regulator and was reported to participate in gastric cancer by regulating MUC5AC promoter [ 38 ].…”

“…Through differential gene-expression analysis and Venn diagram analysis of mRNAs and host genes of circRNAs, we found eight genes in common: in which four gene are tumor-related, including Dock4 , Fmr1 , Zfhx3 , Ralb . These genes have been reported in cancers or tumors in human [ 34 , 37 – 39 ].We characterized circRNA catalogs in chickens, compared them with mRNAs and lncRNAs and found that in chickens, circRNAs have relatively shorter transcripts and similar GC content, these characteristics are similar to lncRNAs in chicken in our previous study [ 46 ]. We also found that one gene could produce multiple circRNAs in chicken, which is consistent with results in human [ 21 ]…”

FMR1 CGG allele length in Israeli BRCA1/BRCA2 mutation carriers and the general population display distinct distribution patterns

“…Yet, unlike the almost complete absence of long CGG repeat sizes (34 repeats and above) in the study by Weghofer and co-workers (2012), in the present study 8·5% of BRCA1/BRCA2 carriers had at least one long CGG allele, a rate that was not statistically different to that of the control population (12·9%). Another recent study that focused on ovarian cancer cases (n = 87) showed that ovarian cancer cases who are BRCA pathogenic mutation carriers (n = 15) exhibit a normal-range prevalence of FMR1 CGG alleles, whereas ovarian cancer patients who are BRCA wildtype, display a trend (not reaching statistical significance) towards higher prevalence of low CGG repeats of the FMR1 gene (Gleicher et al, 2014). In line with our previous data, smaller studies published from Israel (Dagan et al, 2014), Italy (Ricci et al, 2014) and Holland (Brandão et al, 2013) also failed to show the lack of long CGG FMR1 alleles in BRCA mutation carriers.…”

Is Low FMR1 CGG Repeat Length in Males Correlated with Family History of BRCA‐Associated Cancers? An Exploratory Analysis of Medical Records

“…The hypothesis behind this finding is that BRCA1/2 mutations are embryo-lethal but can be rescued by low CGG repeats in the FMR1 gene, and thus women with low CGG repeat length should have an increased risk for BRCA-associated cancers. However, several similar studies have since been conducted and have found no differences in the distribution of FMR1 repeat length between BRCA1/2 mutation carrier women and controls (Dagan et al 2013;Gleicher et al 2014a;Ricci et al 2014). Therefore, a newer hypothesis exists that only certain BRCA1/2 mutations are embryo lethal, requiring rescue by a low FMR1 allele to survive (Gleicher et al 2014b).…”