Premature ovarian insufficiency - the need for a genomic map.

Premature ovarian insufficiency (POI) is a life-long disorder of heterogeneous etiology, presenting as adolescent primary amenorrhea in its most severe form, with an overall incidence of 1%. Idiopathic POI accounts for up to 70% of women with POI; and genomic, genetic, epidemiological, familial and cohort studies demonstrate a genetic component to this condition. Currently, the only genetic tests routinely performed in non-syndromic POI are FMR1 premutation and cytogenetics, the latter specifically for X-chromosome abnormalities. However, a myriad of genetic aberrations has been identified and implicated, some of which act in a monogenic Mendelian fashion. The presence of multiple genetic aberrations and the complexity of POI genomics are hardly surprising since the embryological formation of the primordial oocyte pool, postnatal oogenesis and folliculogenesis are all highly complex pathways. With this review, the aim is to discuss the current genetic etiologies in the emerging field of POI genomics. Promising candidate genes include STAG3, SYCE1, FIGLA, NOBOX, FSHR, BMP15 and INHA. This area has the potential to progress rapidly in light of advances in genomic technologies. The development of a POI genomic map not only will assist in understanding the underlying molecular mechanisms affecting ovarian function but will also be essential in designing predictive and diagnostic gene panels as well as future novel therapeutic strategies.

Mechanism and functional consequences of loss of FOXO1 expression in endometrioid endometrial cancer cells.

The forkhead transcription factor FOXO1, a downstream target of phosphatidylinositol-3-kinase/Akt signalling pathway, regulates cyclic differentiation and apoptosis in normal endometrium, but its role in endometrial carcinogenesis is unknown. Screening of endometrial cancer cell lines demonstrated that FOXO1 is expressed in HEC-1B cells, but not in Ishikawa cells, which in turn highly express the FOXO1 targeting E3-ubiquitin ligase Skp2. FOXO1 transcript levels were also lower in Ishikawa cells and treatment with the proteasomal inhibitor was insufficient to restore expression. Lack of FOXO1 expression in Ishikawa cells was not accounted for by differential promoter methylation or activity, but correlated with increased messenger RNA (mRNA) turnover. Comparative analysis demonstrated that HEC-1B cells proliferate slower, but are more resistant to paclitaxel-mediated cell death than Ishikawa cells, which were partially reversed upon silencing of FOXO1 in HEC-1B cells or its re-expression in Ishikawa cells. We further show that FOXO1 is required for the expression of the growth arrest- and DNA-damage-inducible gene GADD45alpha. Analysis of biopsy samples demonstrated a marked loss of FOXO1 and GADD45alpha mRNA and protein expression in endometrioid endometrial cancer compared to normal endometrium. Together, these observations suggest that loss of FOXO1 perturbs endometrial homeostasis, promotes uncontrolled cell proliferation and increases susceptibility to genotoxic insults.