BRCA1/2 Mutation and FMR1 Gene Study Has Potential Implications for Cancer Screening and Treatment

A new study at a leading infertility clinic explains a gene-mutation paradox and opens doors to a more affordable method of breast and ovarian cancer screening.

BRCA1/2 gene mutations, widely associated with breast and ovarian cancer risks in women, are, in principle, lethal to human embryos, according to new research conducted by three teams of researchers from the Center for Human Reproduction (CHR) in New York City, the Medical University Vienna in Vienna, Austria, and the Medical University Graz, Graz, Austria. BRCA1/2-positive embryos will only survive when also carrying a specific FMR1 gene genotype.

In a paper just published in the prestigious online medical journal PLoS ONE1, the researchers examined the distribution of FMR1 genotypes and sub-genotypes amongst women with BRCA1/2 mutations and in a control population of infertile women. Unexpectedly, almost all the 99 carriers of BRCA1/2 mutations demonstrated a specific FMR1 genotype, the so-called "low" FMR1 allele, defined by less than 26 CGG triple nucleotides. In contrast, over 300 controls presented with a normal distribution of FMR1 genotypes and sub-genotypes.

The authors note that the most likely explanation for such a skewed distribution of FMR1 in BRCA1/2 mutation carriers is embryo lethality of BRCA1/2 in humans; only embryos carrying the "low" FMR1 allele are "rescued" from this embryo-lethality.

"We were very surprised by these results," says David H. Barad, MD, MS, Director of Clinical ART and Senior Scientist at CHR, a senior author of the study. "Since approximately 25% of all women have low FMR1 genotypes, this observation, if confirmed, can greatly impact current cancer screening methods for BRCA1/2-associated cancers in women, and greatly reduce costs."

"These findings also potentially explain the long-unexplained 'BRCA-paradox,'" notes Norbert Gleicher, MD, Medical Director and Chief Scientist of CHR, and another senior author of the study. "BRCA-paradox" refers to the fact that BRCA1/2 mutations are anti-proliferative in embryonic tissue but proliferative in cancer tissues. Dr. Gleicher continues: "Confirmed, these findings could mean that 'low' FMR1 alleles desuppress the antiproliferative activity of BRCA1/2 in both tissues, in embryonic tissues allowing the embryo to survive, while in cancers having the negative effect of allowing cancer to proliferate. This, of course, could open major therapeutic options for improving embryo growth and inhibiting cancer growth."

An Appellate Court recently reaffirmed Myriad Genetics'BRCA1/2 patent. Because of unusually high testing costs for BRCA1/2(ca. $3,000), breast cancer screening and ovarian cancer screening are currently recommended only for women with strong family histories of breast and ovarian cancers. This study suggests the possibility that much less costly FMR1 testing may be able to, at least partially, replace BRCA1/2 testing as a primary screening test. The FMR1 test application utilized in this research is pending U.S. patents, and has been licensed to Women's Laboratory Corporation, LLC, NY, NY.

1Weghofer et al, BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n