Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study

Abstract

BackgroundWe are developing a cross-species comparison strategy to distinguish between cancer driver- and passenger gene alteration candidates, by utilizing the difference in genomic location of orthologous genes between the human and other mammals. As an initial test of this strategy, we conducted a pilot study with human colorectal cancer (CRC) and its mouse model C57BL/6J ApcMin/+, focusing on human 5q22.2 and 18q21.1-q21.2.MethodsWe first performed bioinformatics analysis on the evolution of 5q22.2 and 18q21.1-q21.2 regions. Then, we performed exon-targeted sequencing, real time quantitative polymerase chain reaction (qPCR), and real time quantitative reverse transcriptase PCR (qRT-PCR) analyses on a number of genes of both regions with both human and mouse colon tumors.ResultsThese two regions (5q22.2 and 18q21.1-q21.2) are frequently deleted in human CRCs and encode genuine colorectal tumor suppressors APC and SMAD4. They also encode genes such as MCC (mutated in colorectal cancer) with their role in CRC etiology unknown. We have discovered that both regions are evolutionarily unstable, resulting in genes that are clustered in each human region being found scattered at several distinct loci in the genome of many other species. For instance, APC and MCC are within 200 kb apart in human 5q22.2 but are 10 Mb apart in the mouse genome. Importantly, our analyses revealed that, while known CRC driver genes APC and SMAD4 were disrupted in both human colorectal tumors and tumors from ApcMin/+ mice, the questionable MCC gene was disrupted in human tumors but appeared to be intact in mouse tumors.ConclusionsThese results indicate that MCC may not actually play any causative role in early colorectal tumorigenesis. We also hypothesize that its disruption in human CRCs is likely a mere result of its close proximity to APC in the human genome. Expanding this pilot study to the entire genome may identify more questionable genes like MCC, facilitating the discovery of new CRC driver gene candidates.

miRNA-mRNA Correlation-Network Modules in Human Prostate Cancer and the Differences between Primary and Metastatic Tumor Subtypes

“…Another study [34] also demonstrated that HSV-1 infection in human brain cell can induce the expression of miR-146a. Apparently, these findings not only indicate that miR-146a takes a functional role in immune response as a regulatory factor, but also suggest that its dynamic activity (expression), in some specific contexts, may just serve as the passenger of disease and/or immune processes [10]. This is exactly the main message conveyed by the module p-modu-4-ps where the positive correlations between the modular miRNAs and genes could not be simply explained by a regulator-target mechanism.…”

Frequent Alteration of the Tumor Suppressor Gene APC in Sporadic Canine Colorectal Tumors

“…We performed bi-directional exon-resequencing as previously described [23] to investigate sequence mutations in APC exons in these sporadic canine colorectal tumors. Specifically, we sequenced 14 of the 15 coding exons (as we could not design efficient primers to amplify exon 4) with 8,454 bases total for the canine APC gene, and were able to assemble the entire exon sequences from the forward and reverse sequences of the mostly overlapping PCR products in many cases, as described previously [23].…”

“…Primer design and PCR amplification of exons of the chosen genes, as well as bi-directional sequencing of the PCR products were performed at The J. Craig Venter Institute in Maryland as previously described [23]. Base-calling using the software Phred (www.phrap.org/phredphrapconsed.html), sequence trimming with the software Lucy (www.tigr.org/software/sequencing.shtml), exon sequence assembly, as well as comparison with the published dog reference genome [1] for mutation detection were performed as described [23].…”

“…Base-calling using the software Phred (www.phrap.org/phredphrapconsed.html), sequence trimming with the software Lucy (www.tigr.org/software/sequencing.shtml), exon sequence assembly, as well as comparison with the published dog reference genome [1] for mutation detection were performed as described [23]. A cutoff Phred quality score of 20 was used to reduce false positives due to sequencing errors, ensuring that only high quality bases with an error rate of ≤1% were eligible for mutation findings.…”

The modularity and dynamicity of miRNA–mRNA interactions in high-grade serous ovarian carcinomas and the prognostic implication

“…The involvement of miR-146a in the immune response has been widely investigated. Past studies suggest that miR-146a plays a functional role in immune response as a regulatory factor and its expression may serves as the passenger of disease and/or immune processes (Cameron et al , 2008; Lukiw et al , 2008; Hill et al , 2009; Curtale et al , 2010; Ji et al , 2010). This is exactly the main message conveyed by the module modu-1-ps (as well as the module p-modu-4-ps in (Zhang et al , 2012a)), where the positive correlations between the modular miRNAs and mRNAs could not be simply explained by a regulator-target mechanism.…”