Integrative assessment of CIP2A overexpression and mutational effects in human malignancies identifies possible deleterious variants.

KIAA1524 is the gene encoding the human cancerous inhibitor of PP2A (CIP2A) protein which is regarded as a novel target for cancer therapy. It is overexpressed in 65%-90% of tissues in almost all studied human cancers. CIP2A expression correlates with cancer progression, disease aggressivity in lung cancer besides poor survival and resistance to chemotherapy in breast cancer. Herein, a pan-cancer analysis of public gene expression datasets was conducted showing significant upregulation of CIP2A in cancerous and metastatic tissues. CIP2A overexpression also correlated with poor survival of cancer patients. To determine the non-coding variants associated with CIP2A overexpression, 5'UTR and 3'UTR variants were annotated and scored using RegulomeDB and Enformer deep learning model. The 5'UTR variants rs1239349555, rs1576326380, and rs1231839144 were predicted to be potential regulators of CIP2A overexpression scoring best on RegulomeDB annotations with a high "2a" rank of supporting experimental data. These variants also scored the highest on Enformer predictions. Analysis of the 3'UTR variants of CIP2A predicted rs56255137 and rs58758610 to alter binding sites of hsa-miR-500a-5 and (hsa-miR-3671, hsa-miR-5692a) respectively. Both variants were also found in linkage disequilibrium with rs11709183 and rs147863209 respectively at r2 ≥ 0.8. The aforementioned variants were found to be eQTL hits significantly associated with CIP2A overexpression. Further, analysis of rs11709183 and rs147863209 revealed a high "2b" rank on RegulomeDB annotations indicating a probable effect on DNAse transcription factors binding. The MuTarget analysis indicated that somatic mutations in TP53 are significantly associated with upregulated CIP2A in human cancers. Analysis of missense SNPs on CIP2A solved structure predicted seven deleterious effects. Four of these variants were also predicted as structurally and functionally destabilizing to CIP2A including; rs375108755, rs147942716, rs368722879, and rs367941403. Variant rs1193091427 was predicted as a potential intronic splicing mutation that might be responsible for the novel CIP2A variant (NOCIVA) in multiple myeloma. Finally, Enrichment of the Wnt/ß-catenin pathway within the CIP2A regulatory gene network suggested potential of therapeutic combinations between FTY720 with Wnt/ß-catenin, Plk1 and/or HDAC inhibitors to downregulate CIP2A which has been shown to be essential for the survival of different cancer cell lines.

HIV/AIDS among female sex workers, injecting drug users and men who have sex with men in Lebanon: results of the first biobehavioral surveys.

OBJECTIVES: To measure HIV prevalence and associated risk factors among female sex workers, injecting drug users (IDUs) and men who have sex with men (MSM) in Lebanon and the prevalence of hepatitis B virus and hepatitis C virus among IDUs. METHODS AND DESIGN: A cross-sectional survey of 135 female sex workers, 81 IDUs and 101 MSM was recruited using respondent-driven sampling. A structured interview was conducted by members of nongovernmental organizations working with these populations and blood was collected for serological testing. RESULTS: HIV prevalence was 3.7% among MSM but no HIV cases were detected among female sex workers or IDUs. Among IDUs, prevalence of hepatitis C virus antibody was 51% and prevalence of hepatitis B virus surface antigen was 5%. Three-quarters of MSM had nonregular male sexual partners during the last year but only 39% reported using a condom every time. There was evidence of overlapping HIV risk: 36% of MSM and 12% of IDUs reported that they had sold sex. Previous testing for HIV was lowest among MSM (at 22%) despite their having the highest level both of knowledge about HIV and of perception of being at risk of HIV infection (67%). CONCLUSION: Prevention efforts at greater scale are needed to reach these at-risk populations in Lebanon. These should target MSM in particular, including access to HIV testing, but will need to address and overcome stigma. For IDUs, surveillance and prevention efforts should integrate both hepatitis C virus and HIV.