Clinical importance of the EMSY gene expression and polymorphisms in ovarian cancer

Abstract

EMSY, a BRCA2–associated protein, is amplified and overexpressed in various sporadic cancers. This is the first study assessing the clinical impact of its expression and polymorphisms on ovarian cancer (OvCa) outcome in the context of the chemotherapy regimen used. In 134 frozen OvCa samples, we assessed EMSY mRNA expression with Reverse Transcription-quantitative PCR, and also investigated the EMSY gene sequence using SSCP and/or PCR-sequencing. Clinical relevance of changes in EMSY mRNA expression and DNA sequence was evaluated in two subgroups treated with either taxane/platinum (TP, n=102) or platinum/cyclophosphamide (PC, n=32). High EMSY expression negatively affected overall survival (OS), disease-free survival (DFS) and sensitivity to treatment (PS) in the TP-treated subgroup (p-values: 0.001, 0.002 and 0.010, respectively). Accordingly, our OvCa cell line studies showed that the EMSY gene knockdown sensitized A2780 and IGROV1 cells to paclitaxel. Interestingly, EMSY mRNA expression in surviving cells was similar as in the control cells. Additionally, we identified 24 sequence alterations in the EMSY gene, including the previously undescribed: c.720G>C, p.(Lys240Asn); c.1860G>A, p.(Lys620Lys); c.246-76A>G; c.421+68A>C. In the PC-treated subgroup, a heterozygous genotype comprising five SNPs (rs4300410, rs3814711, rs4245443, rs2508740, rs2513523) negatively correlated with OS (p-value=0.009). The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in OvCa patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well.

PROM1, CXCL8, RUNX1, NAV1 and TP73 genes as independent markers predictive of prognosis or response to treatment in two cohorts of high-grade serous ovarian cancer patients

“…Considering the vast biological diversity of highgrade ovarian cancers, resulting in many apparently discrepant results, as clearly demonstrated herein in the discussion section, the discovery of universal, cohort-independent biomarkers is of paramount importance. As we have shown in our previous research on the CEBPA [2] and EMSY [3] genes, both expression changes and genetic alterations may affect ovarian cancer prognosis and/or response to chemotherapy. The clinical impact of such changes can also be mutually dependent, as observed for example in a nonsense-mediated mRNA decay (NMD), a gene regulatory mechanism which results in low concentrations of mRNAs transcribed from alleles carrying nonsense mutations [4].…”

Clarifying the role of EMSY in DNA repair in ovarian cancer

“…However, this may only be the case when EMSY is coamplified with CCND1 , at least for patients with estrogen receptor–positive breast cancer . In patients with OC, EMSY amplification and messenger RNA (mRNA) overexpression has been previously reported in association with worse survival . However, Hollis et al reported that high EMSY expression was associated with prolonged survival and greater platinum sensitivity in a cohort of 265 high‐grade serous epithelial OC from Edinburgh, as well as multiple publicly available datasets …”

“…11 In patients with OC, EMSY amplification and messenger RNA (mRNA) overexpression has been previously reported in association with worse survival. 7,12 However, Hollis et al reported that high EMSY expression was associated with prolonged survival and greater platinum sensitivity in a cohort of 265 highgrade serous epithelial OC from Edinburgh, as well as multiple publicly available datasets. 13 Amplification of the EMSY gene in OC and other cancer types has been reported to correlate with EMSY mRNA expression in multiple studies, 1,3,4,8 whereas reports regarding the association between EMSY mRNA and protein expression have been limited and conflicting.…”

Genetic Ancestry Analysis Reveals Misclassification of Commonly Used Cancer Cell Lines

“…Effects and mechanisms of genetic, epigenetic, and chemical perturbations on cellular viability are explored in vitro and in vivo through gene knockdown, knockout, and transfection assays using human cell lines (4)(5)(6)(7). Cellular assays employing human cell lines have proven essential to determine the impact of intra-and intergenetic polymorphisms on gene expression and cellular viability (8,9). Although impactful mutations altering gene expression, cell function, or cell viability have been observed, there is significant variability in reproducibility among varying cell lines (10,11).…”