The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Abstract

SUMMARY Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.

PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma

“…Tumor evolution and intratumoral heterogeneity have been extensively studied in ccRCC . These studies demonstrate that mTOR pathway activating mutations can be acquired at different stages of tumor evolution, suggesting a potential impact on rapalog response.…”

Germline variant burden in multidrug resistance transporters is a therapy‐specific predictor of survival in breast cancer patients

“…In all subsequent analysis, only blood samples were considered for the BRCA and LIHC cohort. For the KIRC cohort, we only considered samples classified as ccRCC . As less blood samples were available for this tumor type, we considered both blood samples and tumor‐adjacent normal tissue for genomic analyses.…”

Comprehensive analysis of somatic copy number alterations in clear cell renal cell carcinoma

“…We suggest that the role of SCNAs in invasion/metastasis may vary with the type of cancer. Molecular profiles of tumor cells help to evaluate the carcinogenic course of ccRCC 12 . Although we could classify the ccRCCs we examined into two subgroups (subgroups 1 and 2) in terms of SCNA pattern, there was no significant difference in the SCNA subtypes, including gain, LOH, CN‐LOH, mosaic, and mixed types between subgroups 1 and 2.…”

“…Recently, somatic copy number alterations (SCNAs) have been used to predict tumor aggressiveness in ccRCC 9,10 . Several studies have demonstrated that the presence of multiple SCNAs is associated with overall patient survival, tumor stage, and development of metastasis 11,12 …”

“…Genome‐wide assessment using somatic SCNAs provides useful information for identifying overall genomic profiles of cancer cells 11,12 . The accumulation of SCNAs contributes to tumor heterogeneity and consequently striking differences in the presence of SCNAs between primary and metastatic sites 13 .…”