Research suggests that multiple genes contribute to cancer patientsai??i?? overall survival
Researchers Antoine M Snijders and Jian-Hua Mao from Lawrence Berkeley National Laboratoryai??i??s Biological Systems and Engineering Division in Berkeley, California, United States, in their study published by the journal Advances in Modern Oncology Research (AMOR) sought to compare the amounts of individual mRNAs ai??i?? messenger RNAs that specify the amino acid sequence of the protein products of gene expression ai??i?? in cancerous human tissues with corresponding normal tissues.n integrated quantitative genome data analysis was recently able to pinpoint 18 genes on human chromosome 20q that could potentially serve as novel molecular targets for cancer therapy.
The duo conducted a meta-analysis of genes on chromosome 20q that are found to be consistently upregulated across different human tumor types, while collecting gene transcript data of normal and tumor tissues across 11 different tumor types including brain, breast, colon, gastric, head and neck, liver, lung, ovarian, cervix, pancreas, and prostate cancers.
ai???We calculated the differential expression of all 301 genes present on chromosome 20q for which gene transcript data was available. We then filtered for genes that were upregulated in tumors by at least 1.5 fold (p < 0.05) in seven or more tumor types,ai??? they said.
The resulting analysis identified 18 genes ai??i?? some such as AURKA, UBE2C, TPX2, FAM83D, ZNF217, SALL4 and MMP9 have been previously known to potentially cause cancer. The 18-gene signature is revealed by the study to have robustly elevated levels across human cancers.
ai???We observed significant association of our signature with disease-free survival in all 18 independent dataai??i?? These data indicated that our signature is broadly predictive for disease-free survival, independent of tumor type,ai??? the researchers said.
In certain cases, Snijders and Mao found that increased gene expression was associated with better prognosis. ai???For example, the increased expressions of MMP9 and SULF2 (two neighboring genes) were associated with increased survival in five data sets,ai??? they said.
Mostly, however, their study determined that higher gene expression levels are indicative of poor prognosis in many types of human cancer. For instance, ai???increased expression of RAE1 was associated with decreased disease-free survival in breast, brain, head and neck, lung, ovarian, and pancreatic cancers,ai??? it noted. Likewise, in nine data sets, increased expressions of TPX2, UBE2C, CSE1L and AURKA pointed towards lower disease-free survival.
The researchers were also able to determine that, compared to the genes individually, the expression of the 18-gene signature in its entirety was more significantly associated with cancer patient survival, suggesting that ai???multiple genes independently contribute to the overall survivalai??i?? [which] are consistent with the complex pattern of DNA copy number amplifications often observed on chromosome 20q and the presence of multiple driver genes,ai??? they explained.
Furthermore, using DNA copy number and expression data obtained from The Cancer Genome Atlas project, Snijders and Mao observed that a genetic process called amplification is a major mechanism driving overexpression of these 18 genes in majority of cancers.
Gene amplification is the production of many copies of genes located on a restricted region of the chromosome and it is common in cancer cells. Some amplified genes, according to National Cancer Institute, may even cause cancer cells to proliferate or become resistant to anticancer drugs.
DNA amplifications on chromosome 20q are already often observed in many human cancers, ai???suggesting that genes which reside on chromosome 20q play a causal role in tumorigenesis,ai??? the researchers reported in their study. ai???Moreover, 20q amplifications are often highly complex, indicating the presence of multiple genes is important in tumor development,ai??? they added.
Gene amplifications are under continuous selection pressures, Snijders and Mao described that and ai???when the selection pressure is removed, amplifications are not maintained and eventually disappear. Thus, amplifications focus on those genes that are important for tumor development,ai??? they said.
Their analysis showed that, as tumorous cells progress toward malignancy, the DNA copy number plays a major role in the mechanism of increased expression levels for the 18-gene signature on chromosome 20q. ai???Strong associations between the DNA copy number and gene expression were observed in the majority of tumor types,ai??? the researchers said.
ai???For example, the RAE1 expression was found to be significantly associated with DNA copy number in 20 tumor types,ai??? the study reported. ai???Elevated DNA copy numbers of MMP9 and SULF2 were associated with increased gene expressions in only two and seven tumor types, respectively,ai??? it added.
With their integrated multi-omics analysis of genes on chromosome 20q, Snijders and Mao believed that the 18-gene signature could become new molecular targets for cancer therapy. ai???Gene ontology analysis revealed significant enrichment of cell cycle and mitosis-related biological processes in our 18-gene, suggesting that a cluster of functionally related genes localize to chromosome 20q,ai??? they said.
The identification of good targets such as theirs is a critical step for the development of targeted therapies for cancer treatment, according to the researchers. Microarray and next generation sequencing technologies have become invaluable tools in cataloging genomic abnormalities in human cancers and identifying new potential therapeutic targets, in addition to the availability of large cancer genomic data sets which allows for unbiased approaches to identify genes that are important in tumor progression, the research study noted.
ai???Here, we aggregated available cancer databases to identify cancer driver genes across tumor types by combining gene transcript and DNA copy number across chromosome 20q to select tumor-type specific signatures that predict patient prognosis,ai??? the researchers said. ai???Our strategy identified critical genes and pathways in tumor development that are important for designing better treatment strategies,ai??? they added.
ai???In conclusion, our integrative multi-omics analysis of genes on chromosome 20q is paving the way to the development of additional therapeutic targets for cancers with 20q amplifications. This analysis pipeline could furthermore be potentially applied to other tumor amplicons,ai??? the researchers hoped.
For further in-depth analysis of their study on 18 genes on the chromosome 20q, read Snijders and Maoai??i??s report on AMOR website.