Molecular genomics of bladder cancer


  • Bladder cancers are heterogeneous at the molecular level with two distinct oncogenic pathways.

  • Recent genomic and molecular studies have been focused on muscle invasive bladder cancer (MIBC).

  • Molecular classification based on genetic and molecular alterations characterized by multiple platforms has been proposed for MIBC.

  • Molecular classification is useful for prognostication and therapy response prediction.

Dual-track pathway in bladder carcinogenesis

  • Urothelial cancer (UC) develops via two distinct but somewhat overlapping pathways, papillary and nonpapillary, with low-grade intraurothelial neoplasia (LGIN) as the incipient lesion.

  • Papillary pathway

    • Accounts for approximately 80% of UC

    • LGIN progresses to low-grade and then high-grade papillary UC

    • Enriched with FGFR3 mutations

    • The tumors are often multifocal, superficial, exophytic papillary lesions.

    • The tumors frequently recur after local excision.

    • The tumors usually do not invade the bladder wall or metastasize.

  • Nonpapillary pathway

    • Accounts for the remaining 20% of UC

    • LGIN progresses to UC in situ and then to high-grade invasive UC

    • Enriched with TP53 and RB1 mutations

    • The tumors are usually solid, nonpapillary lesions

    • The tumors often invade the bladder wall and metastasize

    • Patients usually do not have a previous history of papillary UC

  • The overlap between the two pathways

    • 10%–15% of papillary UC eventually progress to high-grade invasive UC.

    • Often preceded by the development of UC in situ within papillary UC or in the adjacent bladder mucosa.

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