Expression in bladder transitional cell carcinoma by real‐time quantitative reverse transcription polymerase chain reaction array of 65 genes at the tumor suppressor locus 9q34.1‐2: Identification of 5 candidates tumor suppressor genes

Abstract

Frequent deletions on 9q34.1-2 were reported in bladder transitional cell carcinoma. High deletion mapping studies delimited a critical interval between markers D9S61 and D9S66, which is highly susceptible to contain a tumor suppressor gene. Expression level of the 65 genes localized in this region was analyzed by real-time quantitative RT-PCR, comparing tumor to normal urothelium. Five genes exhibited a significantly reduced expression level: C9orf9, KIAA0625, ABL1, LAMC3 and KIAA1857-netrin-G2, which exhibited the most significant downregulation (p‫.)7000.0؍‬ KIAA1857-netrin-G2 belongs to the netrins and might then be a tumor suppressor gene in bladder cancer, as netrin1 receptor DCC has been implicated in tumorigenesis. Transitional cell carcinoma (TCC) is the most common form of bladder cancer, accounting for approximately 90% of cases. In 70% of cases, TCC arises as a superficial noninvasive (stage pTa) or lamina propria invasive (stage pT1) disease at initial diagnosis. Chromosome 9 alterations were the earlier and most prevalent genetic alterations in superficial TCC, as it concerned more than 50%, independently of the tumor stage and histological grade. 1,2 The first anomaly found in several cytogenetic and loss of heterozygosity (LOH) studies consisted in monosomy of chromosome 9. 3 However, Simoneau et al., 4 and Van Tilborg et al. 5 found that monosomy was a rare event observed in only 4% and 2.5% of cases, respectively, and interstitial deletions were established on both arms of the chromosome 9. Moreover, several studies showed that allelic losses on 9q were the most frequent and could be observed without concomitant loss on chromosome arm 9p. 4,6 -8 These observations suggested that loss of activity of important genes localized on 9q might be an essential event associated with superficial papillary TCC. Indeed, frequent somatic allelic loss is regarded as a hallmark of tumor suppressor gene (TSG) inactivation. Allelic losses on 9q consequently suggest that inactivation of one or several putative tumor suppressor genes(s) on this chromosome arm would initiate bladder TCC. Several studies reported evidence of at least 3 candidate TSGs on chromosome 9q, based on LOH analysis. Partial 9q deletions pinpoint putative TSGs at 9q12-q22, 9q33 and 9q34 loci. The 9q12-22 region contains the human homologue of the murine growth-arrest-specific gene gas 1, and the PTCH gene, which has been suggested as a TSG in basal cell carcinoma and in bladder cancer; nevertheless mutation of PTCH in bladder TCC was found infrequently. 2,9 Using highdensity deletion mapping with a large number of microsatellites markers, Habuchi et al. 10 identified a candidate TSG in bladder cancer, the DBCCR1 gene (deleted in bladder cancer chromosomal region candidate 1), located between markers D9S103 and GSN at 9q33. Expression of DBCCR1 was found downregulated in bladder cancer cells in vitro, and although no mutation has been detected in bladder tumors, DBCCR1 expression was silenced by promoter hypermethylation in 50% of bladder c...

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