BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?

BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In...

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Autores principales:	Andrea Weghofer, Muy-Kheng Tea, David H Barad, Ann Kim, Christian F Singer, Klaus Wagner, Norbert Gleicher
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3af7a35d30b8432e893273ed6d09e6e7
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spelling	oai:doaj.org-article:3af7a35d30b8432e893273ed6d09e6e72021-11-18T07:05:50ZBRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?1932-620310.1371/journal.pone.0044753https://doaj.org/article/3af7a35d30b8432e893273ed6d09e6e72012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22984553/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG (n<26)) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG (n<26)) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called "BRCA paradox" by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated.Andrea WeghoferMuy-Kheng TeaDavid H BaradAnn KimChristian F SingerKlaus WagnerNorbert GleicherPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e44753 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrea Weghofer Muy-Kheng Tea David H Barad Ann Kim Christian F Singer Klaus Wagner Norbert Gleicher BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?
description	BRCA1/2 mutations and recently described constitutional FMR1 genotypes have, independently, been associated with prematurely diminished ovarian reserve. Whether they interrelate in distribution, and whether observed effects of BRCA1/2 and FMR1 on ovaries are independent of each other, is unknown. In a prospective comparative cohort study, we, therefore, investigated the distribution of constitutional FMR1 genotypes, normal (norm), heterozygous (het) and homozygous (hom), and of their respective sub-genotypes (high/low), in 99 BRCA1/2 mutation-positive women and 410 female controls to determine whether distribution patterns differed between study and control patients. In contrast to controls, BRCA1/2 carriers demonstrated almost complete absence of all constitutional FMR1 genotypes except for sub-genotypes with low (CGG (n<26)) alleles. Cross tabulation between BRCA1/2-positive patients and controls confirmed significant group membership, related to FMR1 distribution (P<0.0001). These results offer as most likely explanation the conclusion that BRCA1/2 mutations are embryo-lethal, unless rescued by low (CGG (n<26)) FMR1 sub-genotypes, present in approximately one quarter of all women. Women with low FMR1 sub-genotypes, therefore, should reflect increased BRCA1/2-associated cancer risks, while the remaining approximately 75 percent should face almost no such risks. If confirmed, this observation offers opportunities for more efficient and less costly BRCA1/2 cancer screening. The study also suggests that previously reported risk towards prematurely diminished ovarian reserve in association with BRCA mutations is FMR1-mediated, and offers a possible explanation for the so-called "BRCA paradox" by raising the possibility that the widely perceived BRCA1/2-associated tumor risk is actually FMR1-mediated.
format	article
author	Andrea Weghofer Muy-Kheng Tea David H Barad Ann Kim Christian F Singer Klaus Wagner Norbert Gleicher
author_facet	Andrea Weghofer Muy-Kheng Tea David H Barad Ann Kim Christian F Singer Klaus Wagner Norbert Gleicher
author_sort	Andrea Weghofer
title	BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?
title_short	BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?
title_full	BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?
title_fullStr	BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?
title_full_unstemmed	BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?
title_sort	brca1/2 mutations appear embryo-lethal unless rescued by low (cgg n<26) fmr1 sub-genotypes: explanation for the "brca paradox"?
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/3af7a35d30b8432e893273ed6d09e6e7
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BRCA1/2 mutations appear embryo-lethal unless rescued by low (CGG n<26) FMR1 sub-genotypes: explanation for the "BRCA paradox"?

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