TGCA pan-cancer analysis

Current clinical practice is organized according to tissue or organ of origin of tumors. Now, The Cancer Genome Atlas (TCGA) Research Network has started to identify genomic and other molecular commonalities among a dozen different types of cancer. Emerging similarities and contrasts will form the basis for _targeted therapies of the future and for repurposing existing therapies by molecular rather than histological similarities of the diseases.

Chris Sander and colleagues have extracted significant functional events from 12 tumor types. Tumors can be classified as being driven largely by either mutation or copy number changes, and, within this division, subclasses of cross-tissue patterns of events are discerned that suggest sets of combinatorial therapies.

Rameen Beroukhim and colleagues analyzed somatic structural alterations in 12 tumor types. Whole-genome doubling was found in over a third of all cancers, associated with TP53 mutation. Fifteen new significantly mutated candidate driver genes were found associated with recurrently amplified or deleted regions.

As the sample size in cancer genome studies increases, the list of genes identified as significantly mutated is likely to include more false positives; here, this problem is identified as stemming largely from mutation heterogeneity, and a new analytical methodology designed to overcome this problem is described.

As part of The Cancer Genome Atlas Pan-Cancer effort, data analysis for point mutations and small indels from 3,281 tumours and 12 tumour types is presented; among the findings are 127 significantly mutated genes from cellular processes with both established and emerging links in cancer, and an indication that the number of driver mutations required for oncogenesis is relatively small.

Viruses contribute to the pathogenesis of certain cancers. Using massively parallel sequencing data from The Cancer Genome Atlas to analyse viral expression in 19 tumour types, Tang et al. both confirm and reject previously described viral associations and present new information on viral integration and host interaction.

Tumour biopsies contain contaminating normal cells and these can influence the analysis of tumour samples. In this study, Yoshihara et al.develop an algorithm based on gene expression profiles from The Cancer Genome Atlas to estimate the number of contaminating normal cells in tumour samples.

Analysis of data from The Cancer Genome Atlas generates a pan-cancer network of 143 recurrent miRNA-_target relationships. The identified miRNAs were frequently regulated by genetic and epigenetic alterations in cancer. The work also reveals that some miRNAs might coordinately regulate cancer pathways, such as miR-29 regulation of TET1 and TDG mRNAs, encoding components from the active DNA demethylation pathway.

IntOGen-mutations is a discovery tool for cancer researchers to find driver mutations in genes and pathways.

This paper reports a strategy for combining somatic mutation profiles of human tumors with gene networks to stratify tumors into biologically and clinically relevant subtypes. The method is applied to ovarian, uterine and lung cancers.

Reuben Harris and colleagues report an analysis of gene expression and mutation data for multiple tumor types. They show that the DNA cytosine deaminase APOBEC3B is upregulated and that its preferred _target sequence is frequently mutated in many types of cancer

Dmitry Gordenin, Gad Getz and colleagues report an analysis of mutation patterns in cancer genomes and find evidence of mutagenesis induced by APOBEC cytidine deaminase enzymes. They find an APOBEC mutagenesis pattern in bladder, cervical, breast, head and neck, and lung cancers, representing 68% of all mutations in some samples.

Larsson Omberg and colleagues write a Commentary describing the collaborative model used by the Pan-Cancer Working Group of The Cancer Genome Atlas. Pan-Cancer members used the Synapse software platform to share and evolve data, results and methods to perform integrative analyses of genome-wide molecular data for 12 cancer types.

Analysis of cancer genomes is moving beyond the confines of a particular disease — researchers are now comparing the genetic and epigenetic characteristics of multiple tumour types. Two scientists comment on what such studies can teach us about cancer biology and how they may guide clinical practice. See Article p.333

With a comprehensive analysis of sequencing data, DNA copy number, gene expression and DNA methylation in a large number of human glioblastomas, The Cancer Genome Atlas project initiative provides a broad overview of the genes and pathways that are altered in this cancer type.

The Cancer Genome Atlas consortium reports on their genome-wide characterization of somatic alterations in colorectal cancer; in addition to revealing a remarkably consistent pattern of genomic alteration, with 24 genes being significantly mutated, the study identifies new _targets for therapeutic intervention and suggests an important role for MYC-directed transcriptional activation and repression.

Comprehensive analyses of 178 lung squamous cell carcinomas by The Cancer Genome Atlas project show that the tumour type is characterized by complex genomic alterations, with statistically recurrent mutations in 11 genes, including TP53 in nearly all samples; a potential therapeutic _target is identified in most of the samples studied.

The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic _target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.