Forerunner Genes: A Novel Class of Early Detection Markers for Bladder CancerIdentification of early changes associated with the development of preneoplastic conditions would provideimportant clue on early events of carcinogenesis and could aid in the development of novel markers for earlyidentification of occult neoplasia. We performed genome-wide search for losses of genetic material onmultiple DNA samples corresponding to normal urothelium, in situ preneoplastic lesions, and invasivecarcinoma extracted from the entire mucosal surface of resected human bladders. The analysis of hitsassociated with growth advantage of preneoplastic lesions allowed us to identify six chromosomal regionsmapping to 3q22.1,5q22.2-5q23.3,9q22.12, 10q26.1, 13q14,and 17p13 that may be critical for thedevelopment of bladder cancer and contain a distinct class of genes referred to as forerunner (FR) genesinvolved in the clonal expansion of precursor conditions. We concentrated our efforts on one of theseregions, which contain a model tumor suppressor RB1. We used high-resolution whole-organ mapping withSNPs, which facilitated the identification of three positional candidate FR genes (ITM2B, P2RY5and CHC1L)mapping contiguously to RB1. We also provide evidence that their inactivation is likely to be critical for thedevelopment of preneoplastic lesions. Using combined genetic and epigenetic mapping of the same regionwe have identified an additional FR gene contiguous to RB1 (GPR38). The expression, mutational, andmethylation analyses showed that at least two of the prototypic FR genes (ITM2B and GPR38) are frequentlymethylated in bladder cancer and their methylation can be detected in voided urine samples. This proposaldescribes our continuing studies focused on the role and function of the prototypic FR gene (ITM2B)contiguous to RB1. Our preliminary data implicate that this gene plays a key role in controlling proliferation ofpreneoplastic clone and is frequently methylated in bladder cancer. Therefore, in addition to the functionalstudies we propose to use the frequently methylated FR genes combined with other methylation markers forthe detection of bladder cancer.
The specific aims for our study are as follows:
Specific Aim 1. Clarify therole and function of the FR gene (ITM2B) in bladder cancer.
Specific Aim 2. Identify an effective methylationpanel of genes, including FR genes for detecting bladder cancer in urine.
Specific Aim 3. Validate themethylation panel of biomarkers in a prospective cohort of patients at high risk of bladder cancer recurrence.
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