Superimposed histologic and genetic mapping of chromosome 9 in progressionof human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer

The evolution of alterations on chromosome 9, including the putative tumor suppressor genes mapped to the 9p21-22 region (the MTS genes), was studied in relation to the progression of human urinary bladder neoplasia by using whole organ superimposed histologic and genetic mapping in cystectomy speci mens and was verified in urinary bladder tumors of various pathogenetic sub sets with longterm follow-up, The applicability of chromosome 9 allelic los ses as non-invasive markers of urothelial neoplasia was tested on voided ur ine and/or bladder washings of patients with urinary bladder cancer, Althou gh sequential multiple hits in the MTS locus were documented in the develop ment of intraurothelial precursor lesions, the MTS genes do not seem to rep resent a major target for p21-23 deletions in bladder cancer, Two additiona l tumor suppressor genes involved in bladder neoplasia located distally and proximally to the MTS locus within p22-23 and p11-13 regions respectively were identified. Several distinct putative tumor suppressor gene loci withi n the q12-13, q21-22, and q34 regions were identified on the q arm. In part icular, the pericentromeric q12-13 area may contain the critical tumor supp ressor gene or genes for the development of early urothelial neoplasia, All elic losses of chromosome 9 were associated with expansion of the abnormal urothelial clone which frequently involved large areas of urinary bladder m ucosa, These losses could be found in a high proportion of urothelial tumor s and in voided urine or bladder washing samples of nearly all patients wit h urinary bladder carcinoma.