Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma
Open accessAbstract
BACKGROUND: 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. METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. RESULTS: 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 MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, 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). CONCLUSIONS: 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.).
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- Authors
- The Cancer Genome Atlas Research Network
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- The Cancer Genome Atlas Research Network
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2016-01-14
- Volume
- 374
- Issue
- 2
- Pages
- 135-145
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4775252
- OpenAlex
- W2111867681
- Cited by
- 1,336
- References
- 42
- Citations by year
- 2026: 60 · 2025: 100 · 2024: 95 · 2023: 130 · 2022: 135 · 2021: 159 · 2020: 153 · 2019: 151 · 2018: 128 · 2017: 126 · 2016: 96 · 2015: 1 · 2014: 2
- FWCI
- 92.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000005)
- National Human Genome Research Institute (U54HG003067, U54HG003079, U54HG003273)
- National Cancer Institute (K24CA172355, U24CA143882, U24CA143843, U24CA143840, U24CA143858, U24CA144025, U24CA143866, U24CA199461, U24CA143883, U24CA143845, U24CA180951, U24CA143867, R01CA169172, U24CA143848, U24CA143799, U24CA143835, P30CA008748, P30CA015083, P30CA016672, P30CA016056, P30CA016086)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- papillary renal cell carcinoma, type 2 papillary renal cell carcinoma, MET alterations, SETD2 mutation, TFE3 fusion, Nrf2/ARE pathway, CpG island methylator phenotype, tumor subtypes, prognosis, molecular heterogeneity
- MeSH terms
- Carcinoma, Papillary, Humans, Kidney Neoplasms, Mutation, Phenotype, RNA, Messenger, RNA, Neoplasm, Signal Transduction, Sequence Analysis, RNA, CpG Islands, DNA Methylation, Proto-Oncogene Proteins c-met, MicroRNAs, NF-E2-Related Factor 2
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