Coexistent intraurothelial carcinoma and muscle-invasive urothelial carcinoma of the bladder: clonality and somatic down-regulation of DNA mismatch repair

Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

“…Core biopsies, obtained for diagnostic purposes, sample only small regions of tumors, and, therefore, are not likely to be informative about the clonal composition of each tumor as a whole. Thus, adequate analysis of intra-tumor clonal heterogeneity often relies on access to post-surgical samples from different regions of tumors [9–11,22,23,30,217]. …”

“…The main limitations would be the heterotypic biology of solid tumors (tumor and nontumor cells coexisting in the neoplasm and the biologic heterogeneity as a byproduct of tumor progression) and the technical aspect to prevent artifacts [4,28,29]. The dynamic nature of neoplasms must be taken into account; there is a continuous selection process of tumor cells that contributes to biologic progression and results in segregation of genetic abnormalities by conditions or topography [10,23–25,30]. Detailed sampling protocols to consider predictable heterogeneity (such as the topographic heterogeneity) and protocols including quality controls for relevant steps during the tests are absolute requirements to have robust results [17,18,28].…”

“…Tumor evolution has often been depicted as successions of initiations and promotions of mutated cells in clonal expansion rounds, where every new round is driven by the acquisition of additional kinetically-advantageous mutational events (selection process) [19]. This sequential process of stochastic acquisition of key mutations drives tumor progression, as a result of proliferation and increased genomic instability that produce progressive selection [9,10,30,32]. Only minority of random mutations are selectively advantageous, while a large fraction of mutations will be discarded by selection.…”

“…The complexity of tumor evolution is further influenced by the ongoing alterations of tumor microenvironment associated with tumor progression, [33] which are likely to alter the selective pressures experienced by tumor cells. Therefore, at the microscopic level, tumor evolution is likely to be non-linear, and substantial genetic heterogeneity is expected in tumor cell populations [10,23,30,31,34]. …”

“…Several intraepithelial foci showed more alterations than matched invasive foci, suggesting a more extensive genetic evolution for the former and supporting multifocality and independent clonal evolution of these coexistent carcinomas. The accumulation of genetic abnormalities in intraepithelial carcinomas is consistent with an advanced molecular stage and progression, along with topographic genetic heterogeneity [23,25,30,31,34,167]. Cancer cells are able to survive and proliferate only at specific secondary sites where there is an ideal environment that releases molecular mediators suitable for that type of cancer cells, still represents a main conceptual model of metastasis in modern cancer research [3,173–175].…”