Comprehensive Molecular Characterization of Papillary Renal Cell Carcinoma

By W. Marston Linehan, P. Spellman, C. Ricketts, Chad Creighton, S. Fei, Caleb F. Davis, D. Wheeler, Bradley A. Murray, L. Schmidt, C. Vocke and 218 more. New England Journal of Medicine, 2015

1,150 citations recorded by the source corpus.

Background Papillary renal cell carcinoma, accounting for 15% of renal cell carcinoma, is a heterogeneous disease consisting of different 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; no effective forms of therapy for advanced disease exist. Methods We performed comprehensive molecular characterization utilizing whole-exome sequencing, copy number, mRNA, microRNA, methylation and proteomic analyses of 161 primary papillary renal cell carcinomas. Results Type 1 and Type 2 papillary renal cell carcinomas were found to be different types of renal cancer characterized by specific genetic alterations, with Type 2 further classified into three individual subgroups based on molecular differences that influenced patient survival. MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene. Conclusions Type 1 and Type 2 papillary renal cell carcinomas are clinically and biologically distinct. Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis. Furthermore, Type 2 papillary renal cell carcinoma consists of at least 3 subtypes based upon molecular and phenotypic features.

Subfields: Epidemiology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/f6252ae4d71a1580734b7723c356ecbffee69577

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In Epidemiology

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Citations in the corpus

• The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. (2016, background): “Recent molecular studies suggest that type 2 papillary RCCs may constitute not a single well-defined entity but rather individual subgroups with different molecular backgrounds [9].”
• Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. (2019, background): “Alterations in the MET pathway were indeed associated with type 1 and activation of the NRF2-ARE pathway was associated with type 2, while CDKN2A loss and a CpG island methylator phenotype in type 2 contributed to convey a poor prognosis [8].”
• Network-based machine learning and graph theory algorithms for precision oncology (2017, background): “97, 109 Finally, the PI3K-Akt pathway has been identi fi ed as one of the most frequently affected pathways in several cancer types, and several components of this pathway were reported to be mutated or ampli fi ed in various cancer types.”
• Treatment of renal cell carcinoma: Current status and future directions (2017, background): “Cytokine-based immunotherapies like IFN-a and IL-2 have proven to be an effective therapeutic modality for a small subset of patients with mRCC. High-dose IL-2 therapy was approved by the FDA based on the pooled results from 7 phase 2 studies conducted in multiple institutions.92 Patients from these”