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TCGA Pan-Cancer Studies Describe New Tumor Features, Subtypes

NEW YORK (GenomeWeb) – A slew of new findings from the Cancer Genome Atlas' Pan-Cancer Initiative are scheduled to appear today in a dozen papers published online in the journal Cell Reports.

For one of the studies, a team from the National Institutes of Health, the Dana-Farber Cancer Institute, the University of California, San Francisco, and other centers reported on findings from a PanCancer Atlas study that investigated mutation, expression, copy number, DNA methylation, microRNA, and other features found in squamous cell carcinoma (SCC) tumors at five sites in the body: the head and neck, lung, esophagus, bladder, and cervix.

In those tumors, which often coincided with a history of smoking or human papillomavirus infection, the researchers narrowed in on sets of recurrent alterations that directed cells toward squamous cell stemness, epithelial-to-mesenchymal transitions, inflammation, and other cellular programs that might ultimately inform the classification and treatment of SCCs.

In another TCGA paper, members of the Pan-Kidney Project presented a molecular analysis of renal cell carcinoma (RCC) based on 843 tumor samples, highlighting specific gene mutations, pathway changes, and metabolic features found in RCC in general and in subtypes such as clear cell RCC, type 1 papillary RCC, type 2 papillary RCC, and chromophobe RCC.

The authors of that study noted that at least some of the alterations identified in the RCC samples seemed to correspond with survival in general, while other prognostic hints were RCC subtype-specific. In chromophobe RCC tumors, for example, the researchers saw diminished survival in cases marked by unusual metabolic profiles.

"Our analyses reveal increasingly discrete characteristics that could lead to a more refined RCC classification, thereby contributing to advances in precision therapy for RCC," the Pan-Kidney investigators wrote. "We also identified unifying features for selected RCC that support the concept of therapeutic approaches that cross disease subtypes."

Focusing on 276 genes with documented roles in DNA damage repair or related pathways, researchers from the Mayo Clinic College of Medicine, the Massachusetts-based pharmaceutical company Tesaro, the University of Washington, and other centers looked at genetic alterations in genes such as TP53 and BRCA1/BRCA2 that are associated with DNA damage repair deficiency in 9,125 tumors from 33 cancer types.

That study offered clues to the biological processes that are upended by these DNA damage repair problems. The team also folded in clinical outcome information to find DNA damage repair patterns that appeared to signal better or worse outcomes. In several cancer types, for example, homology-dependent recombination (HRD) pathway changes were linked to poorer outcomes, though that was not always the case.

Whereas enhanced HRD coincided with shorter progression-free survival times in eight cancer types, the authors noted that "higher HRD scores associated with better clinical outcomes in [glioblastoma multiforme] and [ovarian cancer]."

A Washington University McDonnell Genome Institute-led team focused its analyses on potential driver fusions in the 33 TCGA cancer types, using RNA sequence data, discordant read pair data, gene expression, and other features to profile more than 9,600 tumor samples — an analysis that uncovered tens of thousands of gene fusions in cancer.

"Our study suggests that fusions drive the development of 16.5 percent of cancer cases," authors of that study reported, "and function as the sole driver in more than 1 percent of them."

In addition to recurrent mutations in breast, lung, prostate, and bladder cancers, the researchers identified an over-abundance of kinase fusions in thyroid cancer as well as potentially druggable fusions that include genes such as ALK or RET.

Researchers from the US, France, and Spain focused on cross-cancer mutations that introduced splice site changes using a bioinformatics tool known as MiSplice to identify nearly 2,000 previously missed splice site mutations in 8,656 tumors. For a related study, investigators from the Massachusetts pharma company H3 Biomedicine used exome sequence and RNA sequence data to narrow in on 119 splicing factor genes affected by non-silent mutations across the cancer types assessed through TCGA.

An ISB- and Stony Brook Medicine-led team was able to tease out maps for tumor infiltrating lymphocyte immune cells in 13 of the cancer types, while another team considered the broader immune context for tumors from the TCGA cancer types and subtypes.

Investigators in the US and Taiwan profiled long non-coding RNA regulation, and American, Canadian, and Chinese researchers tallied up metabolic features and subtypes in thousands of of the TCGA tumors.

Still other studies delved into alterations in the pan-cancer set that throw a wrench in specific pathways — from expression, copy number, and mutation patterns linked to enhanced RAS pathway activation to mutations in genes mediating protein ubiquitination dynamics.

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