Deletion mapping implicates two tumor suppressor genes on chromosome 8p in the development of bladder cancer.

Chromosome 8 loss of heterozygosity (LOH) in cancer of the urinary bladder is associated with high tumour grade and stage. We have screened 193 cases of transitional cell carcinoma (TCC) of the bladder using 30 microsatellite polymorphisms on chromosome 8. Forty three cases (22%) showed LOH on 8p, the majority of which (72%) had lost the entire short arm. Using 12 tumours with partial deletions of 8p, we have defined a minimum telomeric region of deletion between D8S264 and D8S133 (8p2l.1-pter). We also found LOH in the region 8pl1.2-12, where we have defined at least one centromeric target for deletion within a 4 cM interval. Two tumours were identified with loss of the telomeric region only, whereas all cases with loss in the centromeric region also had telomeric deletion. Chromosome 8p deletions have also been described in prostate, colorectal, hepatocellular, lung and endometrial carcinoma and collecting duct carcinoma of the kidney. It has been postulated that loss or inactivation of at least 2 tumour suppressor genes on 8p may play an important role in progression of both prostate and colorectal carcinomas. The regions of deletion we have identified in bladder tumours are compatible with these, suggesting that at least two genes on 8p may play a role in the development of many common solid tumours. Our findings significantly refine the localisation of the more centromeric of these loci.

Two novel regions of interstitial deletion on chromosome 8p in colorectal cancer.

We have investigated interstitial deletions of chromosome 8 in 70 colorectal carcinomas and 11 colonic adenomas using 11 microsatellite markers, including eight spanning the centromeric region of chromosome 8p (p11.2-p12). Allelic loss or imbalance was observed in 38 (54%) cancers and four (36%) adenomas. Twenty-eight (40%) of the cancers had deletions of 8p11.2-p12. Two distinct and independent regions of interstitial loss were found within this region. Fluorescent in situ hybridization, using an alpha satellite repeat probe to the centromere of 8p and two probes to the P1 region, was performed in four tumours that demonstrated allelic imbalance. Localized heterozygous deletions were confirmed in all four tumours. Eleven (16%) cancers had localized deletion in the region ANK-1 to D8S255 (P1) and a further eleven (16%) cancers had a less well localized deletion in the region defined by the markers D8S87 to D8S259 (P2). Loss of both centromeric loci was identified in a further six (9%) tumours. A functional significance for these two deletion regions was sought by correlation with primary and secondary tumour characteristics. Isolated P2 deletion was associated with 'early' T1 cancers (2p=0.0002), and were also identified in 3/11 adenomas. Conversely, interstitial deletions of the P1 locus were more frequently seen in 'locally invasive' T3/4 cancers (2p=0.015), and isolated P1 deletions were also associated with the presence of liver metastases (2p=0.016). Our data provide evidence of at least two genes within the 8p11.2-p12 region, mutations in which may confer different and independent roles in the pathogenesis of colorectal cancer.