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TCGA Analysis Points to Kidney Cancer Subtypes With Prognosis, Treatment Clues

NEW YORK (GenomeWeb) – Members of the Cancer Genome Atlas Research Network have described two molecularly distinct types within the kidney cancer papillary renal cell carcinoma, including one group containing three prognostically informative subtypes.

As they reported in the New England Journal of Medicine last night, the researchers used whole-exome sequencing, transcriptome sequencing, microRNA sequencing, proteomic analyses, and array-based methylation and copy number profiling to characterize 161 primary papillary renal cell carcinomas.

Bringing these data together, the researchers defined two main papillary renal cell carcinoma groups: type 1 tumors, which were frequently marked by glitches in the MET gene pathway, and type 2 tumors, which fell into three further subtypes with variable molecular features and patient outcomes.

The findings "really help us understand the phenotypes of sporadic papillary kidney cancer," corresponding author Marston Linehan, a urologic oncology researcher with the National Cancer Institute, told GenomeWeb. "It also confirms that type 1 and type 2 [papillary renal cell carcinoma] really are two very separate diseases."

It's expected that molecular patterns within these groups could help predict disease aggressiveness in papillary renal cell carcinoma patients and, in some cases, highlight possible treatment targets.

Past work indicated the presence of two papillary renal cell carcinoma types as well, the team explained. But the original designations were based mainly on histological tumor features.

The disease — which represents around 15 percent of overall kidney cancers — is known for its heterogeneity, though what was known about it genetically largely stemmed from studies on inherited forms of papillary renal cell carcinoma.

In a Nature Genetics paper published in 1997, for example, Linehan and his colleagues identified mutations in MET — a gene coding for a kidney cell receptor protein that binds a hepatoctype growth factor — in individuals with hereditary papillary renal cell carcinoma, which often shows type 1 histology. Mutations in MET also turned up in a subset of sporadic type 1 cases, hinting at the gene's importance in papillary renal cell carcinoma.

Mutations in other sorts of genes were more common in studies of hereditary leiomyomatosis, a condition that puts individuals at risk of aggressive papillary renal cell carcinoma with type 2 histological features, Linehan explained, including mutations in the gene coding for the fumarate hydratase enzyme.

Nevertheless, researchers suspected additional genetic complexity in sporadic forms of the disease, particularly within type 2 tumors.

For the TCGA analysis, members of the team focused on 161 papillary renal cell carcinoma tumors, including 75 tumors with type 1 histology, 60 tumors that were histologically type 2, and 26 tumors that could not be classified neatly into either group based on histological features.

Using Nimblegen capture kits and the Illumina HiSeq 2000 instrument, they generated exome sequences for matched tumor and normal samples, successfully uncovering almost 10,400 somatic mutations across 157 of the tumors.

The team also used sequencing to assess transcript expression, gene fusions, and miRNA profiles in the tumors and in some adjacent or non-adjacent kidney samples, while Affymetrix and Illumina arrays offered a look at copy number profiles and methylation patterns, and proteomic profiles were produced by reverse phase protein arrays.

Almost one-quarter of the tumors contained mutations in the top five recurrently mutated genes: MET, SETD2, NF2, KDM6A, and SMARCB1. But molecular features differed dramatically between the type 1 and type 2 tumors, as did patient outcomes, Linehan explained.

For example, more than 80 percent of type 1 tumors carried some form of MET pathway alteration, including mutations to MET itself, glitches in genes coding for other components in the pathway, or chromosome 7 gains involving sequences coding for MET and other genes.

Such findings hint that at least some type 1 tumors might be vulnerable to treatments targeting the MET pathway, Linehan noted, such as tyrosine kinase inhibitors — a possibility being explored through ongoing and anticipated clinical trials at NCI and beyond.

Within the type 2 tumors, the researchers saw enhanced NRF2-antioxidant response element (ARE) pathway activity, mutations in the SETD2 gene or other chromatin modifying genes, and fusions involving TFE3 that were previously characterized primarily in kidney cancers affecting children and young adults.

Still, the team found significant heterogeneity and sub-stratification within the three molecular subtypes that made up the group.

The increased NRF2-ARE pathway activity was most pronounced in an aggressive type 2 subtype that had a so-called CpG island methylator phenotype (CIMP), which was marked by hypermethylation increased glycolysis and increased NQO1 gene expression.

CIMP tumors within type 2 were also prone to mutations affecting the fumarate hydratase gene. In the absence of optimal fumarate hydratase, past studies suggest problems may arise with the function of other enzymes, including those tasked with regulating DNA methylation.

Based on available clinical data, the researchers found that the nine individuals with CIMP type 2 tumors had relatively early onset, coupled with the worst papillary renal cell carcinoma outcomes and shortest survival times.

A second subtype of type 2 papillary renal cell carcinoma included 22 cases with slightly better outcomes, though survival times were still diminished compared to those for individuals with type 1 tumors.

This intermediate group included tumors that tended to contain the SETD2 mutations and/or CDKN2A silencing. The remaining 35 type 2 tumors tested fell into a third subtype with survival patterns that were more comparable to the 93 tumors in the type 1 group.

Along with trials focused on exploring targeted treatment options for papillary renal cell carcinoma, Linehan noted that TCGA members are involved in a related effort to do whole-genome sequencing on papillary renal cell carcinoma alongside chromophobe and clear cell renal carcinoma.