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PIWI proteins as prognostic markers in cancer: a systematic review and meta-analysis

By Alexios-Fotios A. Mentis, Efthimios Dardiotis, Athanassios G. Papavassiliou

Posted 14 Jun 2019
bioRxiv DOI: 10.1101/663468 (published DOI: 10.1007/s00018-019-03403-y)

Background: PIWI proteins, which interact with piRNAs, are implicated in stem cell and germ cell regulation, but have been detected in various cancers, as well. Objectives: In this systematic review, we explored, for the first time in the literature (to our knowledge), the association between prognosis in patients with cancer and intratumoral expression of PIWI proteins. Data sources: PubMed, Embase and Web of Knowledge databases were searched for the relevant cohort studies. Study eligibility criteria: Prospective or retrospective cohort studies investigating the association of intratumoral mRNA or protein expression of different types of PIWI proteins with survival, metastasis or recurrence of various types of cancers in the systematic review. Exclusion of cross-sectional studies, of studies on the prognostic value of genetic polymorphism of PIWI genes, of studies re-analyzed previously published databases, and of conference abstracts and non-English articles. Participants: Twenty-six studies with 4,299 participants were included in the systematic review. Interventions: Pooled Hazard Ratios (HRs) and their 95% Confidence Intervals (CIs) were calculated for different PIWI proteins separately, by pooling of log of the calculated HRs using the random-effects model. Study appraisal and synthesis methods: Data extraction was performed using a pre-designed form and quality of the studies was assessed using REMARK criteria. Heterogeneity assessed using the I2 index and the Cochran Q test. Publication bias assessed using funnel plots and Egger's regression. Results: The pooled HR of mortality in high compared to low expression of HIWI, HILI and PIWIL4 was 1.87 (CI95%: 1.31-2.66, p < 0.05), 1.09 (CI95%: 0.58-2.07, p = 0.79) and 0.44 (CI95%: 0.25-0.76, p < 0.05), respectively. The pooled HR of recurrence in in high compared to low expression of HIWI and HILI was 1.72 (CI95%: 1.20-2.49, p < 0.05) and 1.98 (CI95%: 0.65-5.98, p = 0.23), respectively. Limitations: Exclusion of studies not in English; Discrepancy between mRNA and protein levels, and the respective analytical methods; Only one cancer site -PIWI protein pair investigated in three or more studies. Conclusions and Implications of Key Findings: The prognosis of cancer patients is worse with higher HIWI and lower PIWIL4 expression, although the results are highly variable for different cancers. The expression of these proteins can be used for personalized prognostication and treatment of individual patients.

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