Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use.
BACKGROUND
It has been suggested that bladder cancer can be divided into two molecular subtypes referred to as luminal and basal with distinct clinical behaviors and sensitivities to chemotherapy. We aimed to validate these subtypes in several clinical cohorts and identify signature immunohistochemical markers that would permit simple and cost-effective classification of the disease in primary care centers.


METHODS
We analyzed genomic expression profiles of bladder cancer in three cohorts of fresh frozen tumor samples: MD Anderson (n=132), Lund (n=308), and The Cancer Genome Atlas (TCGA) (n=408) to validate the expression signatures of luminal and basal subtypes and relate them to clinical follow-up data. We also used an MD Anderson cohort of archival bladder tumor samples (n=89) and a parallel tissue microarray to identify immunohistochemical markers that permitted the molecular classification of bladder cancer.


RESULTS
Bladder cancers could be assigned to two candidate intrinsic molecular subtypes referred to here as luminal and basal in all of the datasets analyzed. Luminal tumors were characterized by the expression signature similar to the intermediate/superficial layers of normal urothelium. They showed the upregulation of PPARγ target genes and the enrichment for FGFR3, ELF3, CDKN1A, and TSC1 mutations. In addition, luminal tumors were characterized by the overexpression of E-Cadherin, HER2/3, Rab-25, and Src. Basal tumors showed the expression signature similar to the basal layer of normal urothelium. They showed the upregulation of p63 target genes, the enrichment for TP53 and RB1 mutations, and overexpression of CD49, Cyclin B1, and EGFR. Survival analyses showed that the muscle-invasive basal bladder cancers were more aggressive when compared to luminal cancers. The immunohistochemical expressions of only two markers, luminal (GATA3) and basal (KRT5/6), were sufficient to identify the molecular subtypes of bladder cancer with over 90% accuracy.


CONCLUSIONS
The molecular subtypes of bladder cancer have distinct clinical behaviors and sensitivities to chemotherapy, and a simple two-marker immunohistochemical classifier can be used for prognostic and therapeutic stratification.


BACKGROUND
U.S. National Cancer Institute and National Institute of Health.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Vipulkumar
V
Dadhania
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Miao
M
Zhang
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Li
L
Zhang
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Jolanta
J
Bondaruk
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Tadeusz
T
Majewski
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Arlene
A
Siefker-Radtke
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Charles C
CC
Guo
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Colin
C
Dinney
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
David E
DE
Cogdell
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Shizhen
S
Zhang
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Sangkyou
S
Lee
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
June G
JG
Lee
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
John N
JN
Weinstein
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Keith
K
Baggerly
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
David
D
McConkey
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. Electronic address: bczernia@mdanderson.org.
Bogdan
B
Czerniak
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D018295:Neoplasms, Basal Cell / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism* / Q000401:mortality
D014408:Biomarkers, Tumor
Biomarker; Bladder cancer