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.
Department of Pathology, Feinberg School of Medicine, Northwestern University, Illinois, USA.
Ximing J
XJ
Yang
Min-Han
MH
Tan
Hyung L
HL
Kim
Jonathon A
JA
Ditlev
Mark W
MW
Betten
Carolina E
CE
Png
Eric J
EJ
Kort
Kunihiko
K
Futami
Kyle A
KA
Furge
Masayuki
M
Takahashi
Hiro-Omi
HO
Kanayama
Puay Hoon
PH
Tan
Bin Sing
BS
Teh
Chunyan
C
Luan
Kim
K
Wang
Michael
M
Pins
Maria
M
Tretiakova
John
J
Anema
Richard
R
Kahnoski
Theresa
T
Nicol
Walter
W
Stadler
Nicholas G
NG
Vogelzang
Robert
R
Amato
David
D
Seligson
Robert
R
Figlin
Arie
A
Belldegrun
Craig G
CG
Rogers
Bin Tean
BT
Teh
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