Genomic and Functional Regulation of TRIB1 Contributes to Prostate Cancer Pathogenesis

Prostate cancer is the most frequent malignancy in European men and the second worldwide. One of the major oncogenic events in this disease includes amplification of the transcription factor cMYC. Amplification of this oncogene in chromosome 8q24 occurs concomitantly with the copy number increase in a subset of neighboring genes and regulatory elements, but their contribution to disease pathogenesis is poorly understood. Here we show that TRIB1 is among the most robustly upregulated coding genes within the 8q24 amplicon in prostate cancer. Moreover, we demonstrate that TRIB1 amplification and overexpression are frequent in this tumor type. Importantly, we find that, parallel to its amplification, TRIB1 transcription is controlled by cMYC. Mouse modeling and functional analysis revealed that aberrant TRIB1 expression is causal to prostate cancer pathogenesis. In sum, we provide unprecedented evidence for the regulation and function of TRIB1 in prostate cancer.

Population Differentiation at the PVT1 Gene Locus: Implications for Prostate Cancer

Genetic variation in susceptibility to complex diseases, such as cancer, is well-established. Enrichment of disease associated alleles in specific populations could have implications for disease incidence and prevalence. Prostate cancer (PCa) is a disease with well-established higher incidence, prevalence, and worse outcomes among men of African ancestry in comparison to other populations. PCa is a multi-factorial, complex disease, but the exact mechanisms for its development and progression are unclear. The gene desert located on chromosome 8q24 is associated with aggressiveness of PCa. Interestingly, the non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) is present at chromosome 8q24 and is overexpressed in PCa. PVT1 gives rise to multiple transcripts with potentially different molecular and cellular functions. In an analysis of the PVT1 locus using data from the 1000 Genomes Project, we found the chromosomal region spanning PVT1 exons 4A and 4B to be highly differentiated between African and non-African populations. We further investigated levels of gene expression of PVT1 exons 4A and 4B and observed significant overexpression of these exons in PCa tissues relative to benign prostatic hyperplasia and to normal prostate tissues obtained from men of African ancestry. These results indicate that PVT1 exons 4A and 4B may have clinical implications in PCa a conclusion supported by the observation that transient and stable overexpression of PVT1 exons 4A and 4B significantly induce greater prostate epithelial cell migration and proliferation. We anticipate that further exploration of the role of PVT1 exons 4A and 4B may lead to the development of diagnostic, therapeutic, and other clinical applications in PCa.

MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma

Recent studies report that the polarity gene myelin and lymphocyte protein 2 (MAL2), is overexpressed in multiple human carcinomas largely at the transcript level. Because chromosome 8q24 amplification (where MAL2 resides) is associated with hepatocellular- and cholangio-carcinomas, we examined MAL2 protein expression in these human carcinoma lesions and adjacent benign tissue using immunohistochemistry. For comparison, we analyzed renal cell carcinomas that are not associated with chromosome 8q24 amplification. Surprisingly, we found that MAL2 protein levels were decreased in the malignant tissues compared to benign in all three carcinomas, suggesting MAL2 expression may be anti-oncogenic. Consistent with this conclusion, we determined that endogenously overexpressed MAL2 in HCC-derived Hep3B cells or exogenously expressed MAL2 in hepatoma-derived Clone 9 cells (that lack endogenous MAL2) promoted actin-based protrusion formation with a reciprocal decrease in invadopodia. MAL2 overexpression also led to decreased cell migration, invasion and proliferation (to a more modest extent) while loss of MAL2 expression reversed the phenotypes. Mutational analysis revealed that a putative Ena/VASP homology 1 recognition site confers the MAL2-phenotype suggesting its role in tumor suppression involves actin remodeling. To reconcile decreased MAL2 protein expression in human carcinomas and its anti-oncogenic phenotypes with increased transcript levels, we propose a transcriptional regulatory model for MAL2 transient overexpression.

Association of lncRNA CCAT2 and CASC8 Gene Polymorphisms with Hepatocellular Carcinoma

The worldwide incidence of hepatocellular carcinoma (HCC), the major histological type of primary liver cancer, is heterogeneous due to the variable prevalence of etiological factors, indicating a correlation of HCC risk with genetic variations among individuals. Among long non-coding RNAs (lncRNAs) located in the chromosome 8q24 loci and involved in the carcinogenesis are colon cancer associated transcript 2 (CCAT2) and cancer susceptibility candidate 8 (CASC8). In this study, the association of CCAT2 and CASC8 gene polymorphisms with the occurrence of HCC was explored between 397 HCC patients and 1195 controls. We found that carriers of rs6983267 GG in CCAT2 were more susceptible to HCC, with the odds ratio (OR) and adjusted odds ratio (AOR) being 1.532 (95% CI, 1.103–2.129; p = 0.011) and 1.627 (95% CI, 1.120–2.265; p = 0.033), respectively. Moreover, for patients stratified by age (under 65), gender (male only), or status of drinking (habitual drinkers), a protective effect of CASC8 rs3843549 on presenting high Child–Pugh scores, metastatic vascular invasion, or large-size tumors was observed in a dominant model. Collectively, our data reveal association of CCAT2 and CASC8 gene polymorphisms with the occurrence and progression of HCC.

Chromosome 8q24 amplification predicts prognosis for patients with advanced hepatocellular carcinoma (HCC).

e15654 Background: China accounts for over 50% of global liver cancer burden and most patients have advanced disease at the time of diagnosis. Currently, very little is known about the mutational landscape of Chinese HCC patients because it is risky to perform tissue biopsy on late-stage patients. In this study, this problem was overcome by genetic profiling using circulating tumor DNA (ctDNA) and frequently mutated loci were evaluated as biomarkers for prognosis prediction. Methods: Targeted next generation sequencing (NGS) was performed on ctDNA obtained from patients with advanced HCC using a 150-gene panel. The relationship between overall survival (OS) and genetic alterations was analyzed using Kaplan-Meier method. The predictive value of frequently mutated genes was then validated using 607 western HCC cases of the cBioPortal (http://www.cbioportal.org,including TCGA and other two studies). Impact of 8q24 amplification on transcription of other genes was analyzed using mRNA data from TCGA database. Results: Fifty-eight Chinese advanced HCC patients were enrolled and ctDNA was detected in 89.7% of them. The most frequently mutated genes were TP53 (57.7%) and TERT (30.8%) and amplification of chromosome 8q24 occurred at a higher frequency (20.0%) than previously reported for western HCC patients. The 8q24 amplified patients showed significantly shorter OS compared to those without 8q24 amplification (4.9 months vs. Not Reached, p = 0.008). This was confirmed by the cBioPortal database, where 8q24 amplification, which was identified in 10.1% of the HCC cases, was also associated with decreased OS (55.6 months vs.102.7 months, p < 0.001). Gene expression analysis using TCGA mRNA data revealed that upon 8q24 amplification, transcription of 56 genes was upregulated and 169 genes were downregulated, among which ABC transporters, RAS signaling and Hippo signaling pathways were significantly enriched in 8q24 amplified population (p = 0.001, 0.015, 0.027, respectively) as suggested by KEGG analysis. Conclusions: Amplification of chromosome 8q24 ocurred at a higher frequency in Chinese HCC patients and showed promise as a biomarker for prognosis prediction.