Molecular Characterisation Reclassifies Papillary RCC

Papillary renal cell carcinoma type 1 and 2 are characterised by distinct clusters of molecular characteristics and prognosis

medwireNews: Type 1 and 2 papillary renal cell carcinoma (RCC) are two distinct forms of disease, say Cancer Genome Atlas Research Network investigators who have found clear patterns of genetic alterations in this patient population.

Moreover, type 2 papillary RCC patients can be further divided into three groups on the basis of molecular characteristics associated with survival, report W Marston Linehan, from the National Cancer Institute in Bethesda, Maryland, USA, and co-authors in The New England Journal of Medicine.

“This refined classification more accurately reflects the genotypic and phenotypic differences among the various types of these tumors and may lead to more appropriate clinical management and development of more effective forms of therapy”, they write.

Primary papillary RCC samples taken from 161 patients were examined using a raft of molecular techniques, including whole-exome sequencing, messenger RNA and micro RNA sequencing and DNA methylation analysis. This revealed four clusters of tumours.

Cluster 1 was enriched for type 1, stage I or II tumours and was associated with altered METstatus, caused by mutations, splice variants or gene fusion, or gain of chromosome 7, which encodes MET. METalterations were identified in 81% of the type 1 tumours examined.

Cluster 2a comprised predominantly type 2 disease, characterised by early tumour stage and DNA methylation.

In Cluster 2b, all tumours were type 2 or unclassified specimens and were associated with DNA methylation, stage III or IV disease and mutations in the SETD2 gene.

Cluster 2c tumours were characterised by increased DNA methylation at loci but had no such alteration in healthy tissue. “This represents a novel kidney-associated CIMP [CpG island methylator phenotype] that included universal hypermethylation of the CDKN2A promoter”, the authors write.

Patients with Cluster 1 and 2a characteristics had the best overall survival probability, while those in Cluster 2b had an intermediate prognosis. Those with CIMP-associated tumours were diagnosed at a younger age and had poorer overall survival than other papillary RCC patients, they add.

Acknowledging the potential for the current classification to guide clinical and therapeutic decisions, the team observes that METmutations have previously been linked to response to treatment targeting the MET and vascular endothelial growth factor receptor 2 pathways.

In addition, the CIMP-associated tumours show a metabolic shift similar to those of patients with fumarate hydratase-deficient leiomyomatosis and renal cell cancer syndrome. “A clinical trial targeting this metabolic shift in papillary renal-cell carcinoma is currently under way”, the authors note.


Linehan WM, Spellman PT, Ricketts CJ, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med 2015; Advance online publication 4 November.DOI: 10.1056/NEJMoa1505917

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