Mutations in non-tumoral human urothelium: Disease prelude or epilogue?

Abstract

Bladder cancer is characterized by high rates of recurrence and multifocality, features which have commonly been associated with the colonization of widespread areas of non-neoplastic urothelium by mutant cells, a phenomenon known as field change. Whether mutant fields in the bladder arise from tumor cells or develop from the accumulation of somatic mutations followed by clonal expansions of non-transformed progenitor cells during lifetime remains unanswered. In this issue, Strandgaard et al. perform a deep-sequencing analysis of paired samples of tumor and histologically normal-appearing urothelium from four patients with advanced bladder cancer. By using a careful validation process, they report several mutations exclusive of normal, non-neoplastic tissue, suggesting that multiple fields precede (or develop independently from) the disease. Here, we discuss the main results from this work and elaborate on the biological implications and open questions in the context of normal somatic clonal evolution and cancer risk. We finish providing some general guidelines for future experiments to resolve the role of field changes in bladder carcinogenesis and its possible clinical relevance.

Bladder cancer is a highly recurrent disease and frequently presents multifocally, as physically-independent synchronous tumors that often share a clonal origin [1]. These features suggest the existence of a field cancerization effect in the urinary bladder; that is, the presence of genetic alterations in one or various non-neoplastic areas of the tissue that might originate from tumor-derived cells (Fig. 1, left column) or, alternatively, precede the disease (Fig. 1, right column) [1, 2]. While the magnitude of this phenomenon in the urothelium from individuals without bladder cancer remains unclear, so does the extent to which these transformations can be ascribed to the accumulation of somatic mutations in embryonic development or during lifetime, either as a consequence of aging or caused by exposure to carcinogens, which are important questions to be addressed.