Article

Effects of BRCA1 and BRCA2 mutations on female fertility

Department of Family and Consumer Studies, University of Utah, 225 South 1400 East Alfred Emery Building 228, Salt Lake City, UT 84112, USA.
Proceedings of the Royal Society B: Biological Sciences (Impact Factor: 5.05). 04/2012; 279(1732):1389-95. DOI: 10.1098/rspb.2011.1697
Source: PubMed

ABSTRACT

Women with BRCA1/2 mutations have a significantly higher lifetime risk of developing breast or ovarian cancer. We suggest that female mutation carriers may have improved fitness owing to enhanced fertility relative to non-carriers. Here we show that women who are carriers of BRCA1/2 mutations living in natural fertility conditions have excess fertility as well as excess post-reproductive mortality in relation to controls. Individuals who tested positive for BRCA1/2 mutations who linked into multi-generational pedigrees within the Utah Population Database were used to identify putative obligate carriers. We find that women born before 1930 who are mutation carriers have significantly more children than controls and have excess post-reproductive mortality risks. They also have shorter birth intervals and end child-bearing later than controls. For contemporary women tested directly for BRCA1/2 mutations, an era when modern contraceptives are available, differences in fertility and mortality persist but are attenuated. Our findings suggest the need to re-examine the wider role played by BRCA1/2 mutations. Elevated fertility of female mutation carriers indicates that they are more fecund despite their elevated post-reproductive mortality risks.

Download full-text

Full-text

Available from: Ken R Smith
  • Source
    • "The two studies that looked at the parity were questionnaire studies, which also did not have the numbers to address age stratification[57,58]. Interestingly, one study claimed increased fertility in women with BRCA mutations[59]. However, the study was hampered by retrospective design; absence of information on confounding factors, such as smoking and oral contraceptive use; and heterogeneous control (including untested women) and study (including both affected and unaffected carriers and no differentiation of BRCA1 vs. BRCA2 mutations) groups. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oocyte aging has a significant impact on reproductive outcomes both quantitatively and qualitatively. However, the molecular mechanisms underlying the age-related decline in reproductive success have not been fully addressed. BRCA is known to be involved in homologous DNA recombination and plays an essential role in double-strand DNA break (DSB) repair. Given the growing body of laboratory and clinical evidence, we performed a systematic review on the current understanding of the role of DNA repair in human reproduction. We find that BRCA mutations negatively affect ovarian reserve based on convincing evidence from in vitro and in vivo data and prospective studies. Because the decline in the function of the intact gene occurs at an earlier age, women with BRCA1 mutations exhibit accelerated ovarian aging unlike those with BRCA2 mutations. However, because of the still robust function of the intact allele in younger women and due to masking of most severe cases by prophylactic oophorectomy or cancer, it is less likely to see an effect of BRCA mutations on fertility until later in reproductive age. The impact of BRCA2 mutations on reproductive function may be less visible because of the delayed decline in the function of the normal BRCA2 allele. BRCA1 function and ATM-mediated DNA repair may also be important in the pathogenesis of age-induced increase in aneuploidy. BRCA1 is required for meiotic spindle assembly, and cohesion function between sister-chromatids is also regulated by ATM-family member proteins. Taken together, these findings strongly suggest the implication of BRCA and DNA repair malfunction in ovarian aging. Copyright 2015 by The Society for the Study of Reproduction.
    Full-text · Article · Jul 2015 · Biology of Reproduction
  • Source
    • "In the context of cancer, this phenomenon antagonistic pleiotropy -has been found in animal models, perhaps the most stunning case being Xiphophorus fish, where late life melanoma-promoting oncogene alleles are associated with early life advantages (Fernandez and Bowser 2010). There is increasing evidence that some human cancers occurring at later ages may result from negative trade-offs with early age adaptations (Summers and Crespi 2008, 2010; Smith et al. 2012), such as, for instance, high birth weight – a life-history trait that has a genetic basis and is also associated with fitness benefits early in life (e.g., survival until maturity, Thomas et al. 2012b; Smith et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since the mid 1970s, cancer has been described as a process of Darwinian evolution, with somatic cellular selection and evolution being the fundamental processes leading to malignancy and its many manifestations (neoangiogenesis, evasion of the immune system, metastasis, and resistance to therapies). Historically, little attention has been placed on applications of evolutionary biology to understanding and controlling neoplastic progression and to prevent therapeutic failures. This is now beginning to change, and there is a growing international interest in the interface between cancer and evolutionary biology. The objective of this introduction is first to describe the basic ideas and concepts linking evolutionary biology to cancer. We then present four major fronts where the evolutionary perspective is most developed, namely laboratory and clinical models, mathematical models, databases, and techniques and assays. Finally, we discuss several of the most promising challenges and future prospects in this interdisciplinary research direction in the war against cancer.
    Full-text · Article · Jan 2013 · Evolutionary Applications
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most early evolutionary thinkers came from medicine, yet evolution has had a checkered history in medical education. It is only in the last few decades that serious efforts have begun to be made to integrate evolutionary biology into the medical curriculum. However, it is not clear when, where (independently or as part of preclinical or clinical teaching courses) and, most importantly, how should medical students learn the basic principles of evolutionary biology applied to medicine, known today as evolutionary or Darwinian medicine. Most clinicians are ill-prepared to teach evolutionary biology and most evolutionary biologists ill-equipped to formulate clinical examples. Yet, if evolutionary science is to have impact on clinical thought, then teaching material that embeds evolution within the clinical framework must be developed. In this paper, we use two clinical case studies to demonstrate how such may be used to teach evolutionary medicine to medical students in a way that is approachable as well as informative and relevant. KeywordsEvolutionary medicine–Curriculum–Medical education–Case study–Scurvy–Cancers of female reproductive tract–Medical students
    Full-text · Article · Dec 2011 · Evolution Education and Outreach
Show more