We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival ‘neuronal’ subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, lncRNA, and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma-in-situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.
Pancreatic cancer is the eighth most common cancer and has an overall 5-year survival rate lower than 10%. Because of their ability to regulate gene expression, microRNAs can act as oncogenes or tumor-suppressor genes and so have garnered interest as possible prognostic and therapeutic markers during the last decade. However, the prognostic value of microRNA expression in pancreatic cancer has not been thoroughly investigated. We measured the levels of miR-155, miR-203, miR-210, miR-216, miR-217 and miR-222 by quantitative RT-PCR in a cohort of 56 microdissected pancreatic ductal adenocarcinomas (PDAC). These microRNAs were chosen as they had previously been shown to be differentially expressed in pancreatic tumors compared to normal tissues. The possible association of microRNA expression and patients' survival was examined using multivariate Cox's regression hazard analyses. Interestingly, significant correlations between elevated microRNA expression and overall survival were observed for miR-155 (RR 5 2.50; p 5 0.005), miR-203 (RR 5 2.21; p 5 0.017), miR-210 (RR 5 2.48; p 5 0.005) and miR-222 (RR 5 2.05; p 5 0.035). Furthermore, tumors from patients demonstrating elevated expression levels of all 4 microRNAs possessed a 6.2-fold increased risk of tumor-related death compared to patients whose tumors showed a lower expression of these microRNAs. This study provides the first evidence for an oncogenic activity of miR-155, miR-203, miR-210 and miR-222 in the development of pancreatic cancer as has been reported for other tumor types. Furthermore, the putative target genes for these microRNAs suggest a complex signaling network that can affect PDAC tumorigenesis and tumor progression.Because of its poor prognosis, pancreatic cancer is one of the leading causes of cancer-related death, despite its relative low incidence with 9 cases per 100,000 people. 1 The poor prognosis of patients is a result of the late clinical presentation and the high metastatic potential. Three-fourths of pancreatic carcinomas are ductal adenocarcinomas (PDAC). 2 There are molecular prognostic markers known for pancreatic cancers. For example, higher levels of protein expression of VEGF or EGFR have been shown to associate with poorer survival rates. 3 Besides non-physiological KRAS activation, which is mutated in about 95% of all pancreatic carcinomas, 4 inactivation of known tumor-suppressor genes such as p53 or SMAD4 (deleted in 75% or 55% of all PDACs, respectively) have been demonstrated. 5,6 MicroRNAs are small, non-coding RNAs of endogenous origin, which mainly function as negative regulators of gene expression. The association of altered microRNA expression with cancerogenesis as well as tumor progression is well established.  There is a growing number of microRNAs, which are classified as oncogenes or tumor-suppressor genes. 10 For instance, miR-17-92-cluster has gained interest by being regulated via c-myc and its ability to accelerate tumor formation. 11,12 Also, let-7 expression was described to correlate with a poo...
The importance of the p53 stress response pathway in the suppression of tumor formation is well documented. In a previous report, a single nucleotide polymorphism (SNP309 T/G) was found in the promoter of the MDM2 gene resulting in higher levels of MDM2 RNA and protein and, consequently, in the attenuation of the p53 pathway both in vitro and in vivo. As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a welldescribed cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans. Data obtained from patients with three different sporadic cancers, from four independent case studies, support this hypothesis, providing an example for the genetic basis of gender differences in cancer and showing that the genotype at a specific locus can affect how hormones, like estrogen, affect tumorigenesis in humans.
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
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