State of the science: an update on renal cell carcinoma.
Renal cell carcinomas (RCC) are emerging as a complex set of diseases that are having a major socioeconomic impact and showing a continued rise in incidence throughout the world. As the field of urologic oncology faces these trends, several major genomic and mechanistic discoveries are altering our core understanding of this multitude of cancers, including several new rare subtypes of renal cancers. In this review, these new findings are examined and placed in the context of the well-established association of clear cell RCC (ccRCC) with mutations in the von Hippel-Lindau (VHL) gene and resultant aberrant hypoxia inducible factor (HIF) signaling. The impact of novel ccRCC-associated genetic lesions on chromatin remodeling and epigenetic regulation is explored. The effects of VHL mutation on primary ciliary function, extracellular matrix homeostasis, and tumor metabolism are discussed. Studies of VHL proteostasis, with the goal of harnessing the proteostatic machinery to refunctionalize mutant VHL, are reviewed. Translational efforts using molecular tools to elucidate discriminating features of ccRCC tumors and develop improved prognostic and predictive algorithms are presented, and new therapeutics arising from the earliest molecular discoveries in ccRCC are summarized. By creating an integrated review of the key genomic and molecular biological disease characteristics of ccRCC and placing these data in the context of the evolving therapeutic landscape, we intend to facilitate interaction among basic, translational, and clinical researchers involved in the treatment of this devastating disease, and accelerate progress toward its ultimate eradication.
MD Anderson Cancer Center, Houston, Texas, USA.
Eric
E
Jonasch
P Andrew
PA
Futreal
Ian J
IJ
Davis
Sean T
ST
Bailey
William Y
WY
Kim
James
J
Brugarolas
Amato J
AJ
Giaccia
Ghada
G
Kurban
Armin
A
Pause
Judith
J
Frydman
Amado J
AJ
Zurita
Brian I
BI
Rini
Pam
P
Sharma
Michael B
MB
Atkins
Cheryl L
CL
Walker
W Kimryn
WK
Rathmell
D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D044127:Epigenesis, Genetic / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009154:Mutation; D057170:Translational Research, Biomedical; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human