Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Papillary renal-cell carcinoma (PRCC) is a heterogeneous kidney cancer subtype.
• Existing knowledge on the genetic basis of sporadic PRCC and effective therapies for advanced stages is limited.

Purpose of the Study:

• To conduct comprehensive molecular characterization of PRCC.
• To identify distinct molecular subtypes within PRCC and their association with patient outcomes.

Main Methods:

• Whole-exome sequencing
• Copy-number analysis
• RNA and microRNA sequencing
• DNA-methylation analysis
• Proteomic analysis

Main Results:

• PRCC types 1 and 2 exhibit distinct genetic alterations.
• Type 2 PRCC can be subclassified into three molecular subgroups impacting survival.
• Type 1 tumors show MET alterations; Type 2 tumors display CDKN2A silencing, SETD2 mutations, TFE3 fusions, and NRF2-ARE pathway activation.
• A distinct subgroup of type 2 PRCC with poor survival is characterized by CpG island methylator phenotype (CIMP) and FH gene mutations.

Conclusions:

• Type 1 and Type 2 PRCC are clinically and biologically distinct entities.
• MET pathway alterations are associated with Type 1 PRCC.
• NRF2-ARE pathway activation, CDKN2A loss, and CIMP in Type 2 PRCC indicate a poor prognosis.
• Type 2 PRCC comprises at least three molecular subtypes.