Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia.
We used human bladder cancer as a model system and the whole-organ histologic and genetic mapping strategy to identify clonal genetic hits associated with growth advantage, tracking the evolution of bladder cancer from intraurothelial precursor lesions. Six putative chromosomal regions critical for clonal expansion of intraurothelial neoplasia and development of bladder cancer were identified by using this approach. Focusing on one of the regions, which includes the model tumor suppressor RB1, we performed allelotyping of single-nucleotide polymorphic sites and identified a 1.34-Mb segment around RB1 characterized by a loss of polymorphism associated with the initial expansion of in situ neoplasia. This segment contains several positional candidate genes referred to by us as forerunner genes that may contribute to such expansion. We subsequently concentrated our efforts on the two neighbor genes flanking RB1, namely ITM2B and CHC1L, as well as P2RY5, which is located inside RB1. Here, we report that ITM2B and P2RY5 modulated cell survival and were silenced by methylation or point mutations, respectively, and thus by functional loss may contribute to the growth advantage of neoplasia. We also show that homozygous inactivation of P2RY5 was antecedent to the loss of RB1 during tumor development, and that nucleotide substitutions in P2RY5 represent a cancer predisposing factor.
Lee
Sangkyou
S
Department of Pathology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Jeong
Joon
J
Majewski
Tadeusz
T
Scherer
Steven E
SE
Kim
Mi-Sook
MS
Tuziak
Tomasz
T
Tang
Kuang S
KS
Baggerly
Keith
K
Grossman
Herbert Barton
HB
Zhou
Jain-Hua
JH
Shen
Lanlan
L
Bondaruk
Jolanta
J
Ahmed
Saira S
SS
Samanta
Susmita
S
Spiess
Philippe
P
Wu
Xifeng
X
Filipek
Slawomir
S
McConkey
David
D
Bar-Eli
Menashe
M
Issa
Jean-Pierre
JP
Benedict
William F
WF
Czerniak
Bogdan
B
D001483:Base Sequence; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008958:Models, Molecular; D011110:Polymorphism, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
D018048:Receptors, Purinergic P2; D016160:Retinoblastoma Protein
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