Common Human Cancer Genes Discovered by Integrated Gene-Expression Analysis

Abstract

BackgroundMicroarray technology enables a standardized, objective assessment of oncological diagnosis and prognosis. However, such studies are typically specific to certain cancer types, and the results have limited use due to inadequate validation in large patient cohorts. Discovery of genes commonly regulated in cancer may have an important implication in understanding the common molecular mechanism of cancer.Methods and FindingsWe described an integrated gene-expression analysis of 2,186 samples from 39 studies to identify and validate a cancer type-independent gene signature that can identify cancer patients for a wide variety of human malignancies. The commonness of gene expression in 20 types of common cancer was assessed in 20 training datasets. The discriminative power of a signature defined by these common cancer genes was evaluated in the other 19 independent datasets including novel cancer types. QRT-PCR and tissue microarray were used to validate commonly regulated genes in multiple cancer types. We identified 187 genes dysregulated in nearly all cancerous tissue samples. The 187-gene signature can robustly predict cancer versus normal status for a wide variety of human malignancies with an overall accuracy of 92.6%. We further refined our signature to 28 genes confirmed by QRT-PCR. The refined signature still achieved 80% accuracy of classifying samples from mixed cancer types. This signature performs well in the prediction of novel cancer types that were not represented in training datasets. We also identified three biological pathways including glycolysis, cell cycle checkpoint II and plk3 pathways in which most genes are systematically up-regulated in many types of cancer.ConclusionsThe identified signature has captured essential transcriptional features of neoplastic transformation and progression in general. These findings will help to elucidate the common molecular mechanism of cancer, and provide new insights into cancer diagnostics, prognostics and therapy.

p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control

“…A plausible candidate that fits this criterion is the RORa1-binding site in the positive regulatory region of the LIMK2b promoter (Nomoto et al, 1999). In support, RORa mRNA is often downregulated in tumor cell lines and cancers (Zhu et al, 2006;Lu et al, 2007;Jetten 2009), and its expression is upregulated by a variety of genotoxic stresses (Zhu et al, 2006). Whether this latter function also includes coactivation with p53, for example, in the transactivation of LIMK2b, remains to be determined.…”

Tumor cell metabolism

“…5 Microarray data sets collected from several studies have consistently shown most of the genes involved in glucose transport and glycolysis to be upregulated in different types of tumors. 9,16,17 Glucose transporters are overexpressed in hepatocarcinomas, breast cancer, neuroendocrine carcinomas, lymphoblastic leukemia and others. [18][19][20][21] It has been proposed that the high glucose uptake in cancer cells favors cell proliferation more than energy production because glucose metabolism mainly supports fatty acid and ribose-5-phosphate synthesis 5,22 ( Fig.…”

“…Glycolytic genes like TPI1, PGK1, ENOa, PK-M2, ALDO-A, GPI and PDHA1 were also found to be significantly upregulated in most of the 20 different types of common cancer examined, regardless of their tissue origin. 17 The substantial increase in the glycolytic flux of cancer cells is caused, in part, by the activation of the regulatory bi-functional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) enzyme. 23 Fructose-2,6-bisphosphate (F2,6BP) is synthesized by the PFKFB enzyme; F2,6BP is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), which is a rate-limiting enzyme that is an essential control point in the glycolytic pathway.…”

FBG1 is a promiscuous ubiquitin ligase that sequesters APC2 and causes S-phase arrest

“…cancer cells. 53,54 Examination of GEO expression profiles 55 accession GSE3189 revealed that FBG1 is downregulated in melanomas. Fourth, this ubiquitin ligase degrades the adhesion receptor SHPS-1, which may be involved in tumor metastasis in melanomas and other cancers.…”