Posts Tagged ‘subclasses’

Renal Cell Carcinoma Classified

Larry H. Bernstein, MD, FCAP, Curator



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.


Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

The Cancer Genome Atlas Research Network Group

NEJM   Nov 4, 2015     DOI: http://dx.doi.org:/10.1056/NEJMoa1505917

Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with METalterations, whereas type 2 tumors were characterized by CDKN2Asilencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2–antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).

Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.)

Figure 1. Somatic Alterations in Papillary Renal-Cell Carcinoma and Molecular Differences between Type 1 and Type 2 Cancers.


Unsupervised clustering of DNA copy profiles of 161 papillary renal-cell carcinomas (PRCCs) (Panel A) revealed three molecular subtypes, one of which was highly enriched for type 1 tumors and the other two for type 2 tumors. SCNA denotes somatic copy-number alterations. Significantly mutated genes (SMGs) in PRCC (Panel B) were determined by considering all genes (q<0.1 [range, 0.0 to 1.0]) or focusing on the set of 260 genes previously implicated in cancer by large-scale, pan-cancer exome analyses15 (q<0.1). P values were calculated with the MutSigCV algorithm, version 2.0. A pathway-centric view of gene mutations in PRCC (Panel C) shows key pathways and genes implicated in cancer, either in the current study or elsewhere.15 The tumors were classified according to histologic type (from left to right) and according to gene or pathway altered (from top to bottom). Pathways and genes represented include MET, the Hippo pathway (NF2, SAV1, and WWC1), the NRF2 pathway (NFE2L2, KEAP1, CUL3, SIRT1, and FH), chromatin modification (CREBBP, DOTL1, EHMT1/2, EP300, EZH1/2, KAT2A/B, KDM1A/B, KDM4A/B, KDM5A/B/C, KDM6A/B, MLL1/2/3/4/5, NSD1, SETD2, SMYD4, and SRCAP), the SWI/SNF complex (ACTB, ACTL6A/B, ARID1A/B, ARID2, BCL6A/B/C, BCL11A/B, BRD7/9, DPF1/2/3, PHF10, PBRM1, SMARCA2/4

Figure 2. Alterations in Papillary Renal-Cell Carcinoma Involving the MET Oncogene.


Panel A is a schematic representation of somatic mutations in MET, along with germline variant H1112R, which was previously implicated in hereditary papillary renal-cell carcinoma,17 and the novel RNA transcript variant of MET lacking the canonical exons 1 and 2 but containing a novel exon 1 that splices to the canonical exon 3. IPT denotes immunoglobulin-like, plexins, and transcription factors, and PSI plexins, semaphorins, and integrins. Panel B shows the crystal structure for the MET tyrosine kinase catalytic domain (RCSB-PDB 3I5 N18), on which are mapped the residues that are altered in papillary renal-cell carcinoma. All numbering of amino acids is based on the MET protein sequences.

We used a comprehensive genomics approach to characterize the biologic foundation of papillary renal-cell carcinoma and found that type 1 and type 2 papillary renal-cell carcinoma are distinctly different diseases and that type 2 papillary renal-cell carcinoma is a heterogeneous disease with multiple distinct subgroups. Common driver mutations among the different subtypes were relatively rare, as had been observed in two recent studies.7,30 Molecular and phenotypic differences between type 1 and type 2 papillary renal-cell carcinoma were reflected in individual and combined analyses of various data platforms. The usefulness of CDKN2A alterations as an independent prognostic marker associated with type 2 tumors requires validation. This study suggests that gene fusions involving TFE3 or TFEB are underappreciated in type 2 tumors in adults and should be considered in any patient with type 2 disease. Although papillary renal-cell carcinomas with fusions involving TFE3 or TFEB are generally considered to be diseases of children and young adults,16the mean age in our study was 52 years, and we found tumors with TFEB fusions in patients 64 and 71 years of age.

The most distinct of the three type 2 subgroups was the subgroup defined by the CIMP, which was associated with the worst overall survival. CIMP hypermethylation patterns have been observed in a number of other cancer subtypes, including glioblastoma,31 lung adenocarcinoma,32 and gastric adenocarcinoma.33 The CIMP-associated tumors showed low levels of FH mRNA expression, and five had germline or somatic mutation of FH. Germline mutation of FH has been observed in the aggressive type 2 tumor associated with the hereditary leiomyomatosis and renal-cell cancer syndrome.9,34 In this syndrome, the high levels of fumarate accumulating from loss of fumarate hydratase enzyme activity result in impaired function of enzymes such as the TET family of enzymes, which play a role in maintaining appropriate DNA methylation within the genome.35 The subgrouping of type 2 tumors according to molecular features and the presence of specific subsets of type 2 tumors, such as those with TFE3 fusions or CIMP, suggest that substratification of type 2 papillary renal-cell carcinoma according to specific molecular markers may allow more accurate diagnosis that could lead to the development of mechanistic, disease-specific targeted therapies.

This classification of papillary renal-cell carcinoma could potentially have a substantial effect on clinical and therapeutic management and on the design of clinical trials. Alteration of MET or gain of chromosome 7 was observed in a large percentage (81%) of type 1 tumors. Antitumor activity of an agent targeting the MET and VEGFR2 pathways has been shown in a phase 2 trial involving patients with papillary renal-cell carcinoma, with a particularly high response rate among patients who had tumors with MET mutations.36 Mutation of the Hippo pathway tumor suppressor, NF2, was observed in a number of papillary renal-cell carcinomas. This pathway has been targeted in other cancers with agents such as dasatinib, an inhibitor of the YES1 kinase that interacts with the YAP transcription factor that is up-regulated with Hippo pathway dysregulation.37 The CIMP-associated tumors showed a Warburg-like metabolic shift, similar to that observed in fumarate hydratase–deficient tumors in patients with the hereditary leiomyomatosis and renal-cell cancer syndrome.11,25,26 A clinical trial targeting this metabolic shift in papillary renal-cell carcinoma is currently under way (ClinicalTrials.gov number, NCT01130519). Increased expression of the NRF2-ARE pathway has been observed in both hereditary and sporadic type 2 papillary renal-cell carcinomas.12 Immunohistochemical analysis for NQO1 could provide a valuable marker of activation of the NRF2-ARE pathway. Currently, there is intense interest in the NRF2-ARE pathway in cancer,38 and novel strategies have recently been developed to target this pathway.39

The identification of altered genes and pathways provides a comprehensive foundation for an understanding of the molecular basis of papillary renal-cell carcinoma. 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.

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