A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.The QIMR Berghofer groups were supported by a Rio Tinto Ride to Conquer Cancer (RTCC)/Weekend to End Women's Cancers (WEWC) Grant and NHMRC project grants 1058415 to SLE and 1031333 to ABS. ABS is supported by an NHMRC Senior Research Fellowship (1061779). DFE is a Principal Research Fellow of CR-UK.This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Cell Press

PIK3CA mutations and their impact on survival outcomes of patients with endometrial cancer: A systematic review and meta-analysis.

Several studies have highlighted the frequent alterations of the PI3K pathway in endometrial cancer leading to increased signaling activation with potential for targeted treatment. The objective of this meta-study was to evaluate how PIK3CA exon 9/20 mutations affect survival in endometrial cancer patients, based on available literature. Topic-based search strategies were applied to databases including CENTRAL, MEDLINE, Embase, Web of Science and COSMIC. All studies assessing the impact of mutations in exon 9 and exon 20 of PIK3CA on survival rates of endometrial cancer patients were selected for inclusion. Statistical meta-analysis was performed with the 'meta' package in RStudio. Overall, 7 of 612 screened articles were included in the present study, comprising 1098 women with endometrial cancer. Meta-analysis revealed a tendency of impaired survival for patients with PIK3CA exon 9 and/or exon 20 mutations (RR 1.28; 95% CI 0.84, 1.94; p = 0.25). This tendency was consistent in subgroup analyses stratified by histologic type or -grade, with the most prominent effect in low-grade endometrial cancers (RR 2.04; 95% CI 0.90, 4.62; p = 0.09). In summary, these results suggest that PIK3CA mutations negatively influence survival outcomes of patients with endometrial cancer, including those with low-grade tumors

Modified Newcastle-Ottawa quality assessment scale and scoring algorithm.

Modified Newcastle-Ottawa quality assessment scale and scoring algorithm.</p

Funnel plot.

Funnel plot of the estimation of publication bias on the effect of PIK3CA exon 9 and exon 20 mutations on survival outcomes of endometrial cancer patients. (DOCX)</p

PRISMA 2009 checklist.

Several studies have highlighted the frequent alterations of the PI3K pathway in endometrial cancer leading to increased signaling activation with potential for targeted treatment. The objective of this meta-study was to evaluate how PIK3CA exon 9/20 mutations affect survival in endometrial cancer patients, based on available literature. Topic-based search strategies were applied to databases including CENTRAL, MEDLINE, Embase, Web of Science and COSMIC. All studies assessing the impact of mutations in exon 9 and exon 20 of PIK3CA on survival rates of endometrial cancer patients were selected for inclusion. Statistical meta-analysis was performed with the ‘meta’ package in RStudio. Overall, 7 of 612 screened articles were included in the present study, comprising 1098 women with endometrial cancer. Meta-analysis revealed a tendency of impaired survival for patients with PIK3CA exon 9 and/or exon 20 mutations (RR 1.28; 95% CI 0.84, 1.94; p = 0.25). This tendency was consistent in subgroup analyses stratified by histologic type or -grade, with the most prominent effect in low-grade endometrial cancers (RR 2.04; 95% CI 0.90, 4.62; p = 0.09). In summary, these results suggest that PIK3CA mutations negatively influence survival outcomes of patients with endometrial cancer, including those with low-grade tumors.</div

Summary of included studies.

Several studies have highlighted the frequent alterations of the PI3K pathway in endometrial cancer leading to increased signaling activation with potential for targeted treatment. The objective of this meta-study was to evaluate how PIK3CA exon 9/20 mutations affect survival in endometrial cancer patients, based on available literature. Topic-based search strategies were applied to databases including CENTRAL, MEDLINE, Embase, Web of Science and COSMIC. All studies assessing the impact of mutations in exon 9 and exon 20 of PIK3CA on survival rates of endometrial cancer patients were selected for inclusion. Statistical meta-analysis was performed with the ‘meta’ package in RStudio. Overall, 7 of 612 screened articles were included in the present study, comprising 1098 women with endometrial cancer. Meta-analysis revealed a tendency of impaired survival for patients with PIK3CA exon 9 and/or exon 20 mutations (RR 1.28; 95% CI 0.84, 1.94; p = 0.25). This tendency was consistent in subgroup analyses stratified by histologic type or -grade, with the most prominent effect in low-grade endometrial cancers (RR 2.04; 95% CI 0.90, 4.62; p = 0.09). In summary, these results suggest that PIK3CA mutations negatively influence survival outcomes of patients with endometrial cancer, including those with low-grade tumors.</div

Quality assessment of the included studies according to the Newcastle-Ottawa Scale.

Quality assessment of the included studies according to the Newcastle-Ottawa Scale.</p

Characteristics of patients enrolled in included studies.

Characteristics of patients enrolled in included studies.</p

Meta-analysis results of the effect of <i>PIK3CA</i> mutations on EC patient survival in relation to grade.

Forest plots visualizing relative risks (RR) of combined overall and disease-specific survival in the a) low-grade and b) high grade subgroups.</p

Meta-analysis results of the effect of <i>PIK3CA</i> mutations on EC patient survival.

Forest plot visualizing relative risks (RR) of combined overall and disease-specific survival among studies included. Grey boxes represent relative risk of individual studies, with box size representing the inverse of the variance in individual studies and vertical black lines representing 95% confidence intervals. The diamonds represent the summarized effect of the PIK3CA mutation on survival for both the common effects and random effects models.</p