Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy.
The search for the genomic sequences involved in human cancers can be greatly facilitated by maps of genomic imbalances identifying the involved chromosomal regions, particularly those that participate in the development of occult preneoplastic conditions that progress to clinically aggressive invasive cancer. The integration of such regions with human genome sequence variation may provide valuable clues about their overall structure and gene content. By extension, such knowledge may help us understand the underlying genetic components involved in the initiation and progression of these cancers. We describe the development of a genome-wide map of human bladder cancer that tracks its progression from in situ precursor conditions to invasive disease. Testing for allelic losses using a genome-wide panel of 787 microsatellite markers was performed on multiple DNA samples, extracted from the entire mucosal surface of the bladder and corresponding to normal urothelium, in situ preneoplastic lesions, and invasive carcinoma. Using this approach, we matched the clonal allelic losses in distinct chromosomal regions to specific phases of bladder neoplasia and produced a detailed genetic map of bladder cancer development. These analyses revealed three major waves of genetic changes associated with growth advantages of successive clones and reflecting a stepwise conversion of normal urothelial cells into cancer cells. The genetic changes map to six regions at 3q22-q24, 5q22-q31, 9q21-q22, 10q26, 13q14, and 17p13, which may represent critical hits driving the development of bladder cancer. Finally, we performed high-resolution mapping using single nucleotide polymorphism markers within one region on chromosome 13q14, containing the model tumor suppressor gene RB1, and defined a minimal deleted region associated with clonal expansion of in situ neoplasia. These analyses provided new insights on the involvement of several non-coding sequences mapping to the region and identified novel target genes, termed forerunner (FR) genes, involved in early phases of cancer development.
Majewski
Tadeusz
T
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Lee
Sangkyou
S
Jeong
Joon
J
Yoon
Dong-Sup
DS
Kram
Andrzej
A
Kim
Mi-Sook
MS
Tuziak
Tomasz
T
Bondaruk
Jolanta
J
Lee
Sooyong
S
Park
Weon-Seo
WS
Tang
Kuang S
KS
Chung
Woonbok
W
Shen
Lanlan
L
Ahmed
Saira S
SS
Johnston
Dennis A
DA
Grossman
H Barton
HB
Dinney
Colin P
CP
Zhou
Jain-Hua
JH
Harris
R Alan
RA
Snyder
Carrie
C
Filipek
Slawomir
S
Narod
Steven A
SA
Watson
Patrice
P
Lynch
Henry T
HT
Gazdar
Adi
A
Bar-Eli
Menashe
M
Wu
Xifeng F
XF
McConkey
David J
DJ
Baggerly
Keith
K
Issa
Jean-Pierre
JP
Benedict
William F
WF
Scherer
Steven E
SE
Czerniak
Bogdan
B
D000368:Aged; D002295:Carcinoma, Transitional Cell / Q000235:genetics*; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016160:Retinoblastoma Protein / Q000235:genetics; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000235:genetics*; D019459:Urothelium / Q000378:metabolism / Q000473:pathology
D016160:Retinoblastoma Protein