A molecular classification of papillary renal cell carcinoma.
Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIalpha in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.
Yang
Ximing J
XJ
Department of Pathology, Feinberg School of Medicine, Northwestern University, Illinois, USA.
Tan
Min-Han
MH
Kim
Hyung L
HL
Ditlev
Jonathon A
JA
Betten
Mark W
MW
Png
Carolina E
CE
Kort
Eric J
EJ
Futami
Kunihiko
K
Furge
Kyle A
KA
Takahashi
Masayuki
M
Kanayama
Hiro-Omi
HO
Tan
Puay Hoon
PH
Teh
Bin Sing
BS
Luan
Chunyan
C
Wang
Kim
K
Pins
Michael
M
Tretiakova
Maria
M
Anema
John
J
Kahnoski
Richard
R
Nicol
Theresa
T
Stadler
Walter
W
Vogelzang
Nicholas G
NG
Amato
Robert
R
Seligson
David
D
Figlin
Robert
R
Belldegrun
Arie
A
Rogers
Craig G
CG
Teh
Bin Tean
BT
D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002869:Chromosome Aberrations; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000145:classification* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis