High throughput molecular diagnostics in bladder cancer - on the brink of clinical utility

Abstract

An enormous body of high-throughput genome-wide data, in particular gene expression data, has been gathered from roughly all human cancer forms in the past 10 years. This has widely increased our understanding of the cancer disease and its molecular changes and pathways, with a large contribution from studies of cancer cell lines and functional genomics. In the last three years, the focus has been moved to clinical outcome parameters as recurrence, progression, metastasis and treatment response. The huge variability of molecular changes and poor availability of samples have hampered progress in the field of epithelial cancer (carcinoma). However, independent validation of molecular profiles across high-throughput platforms, methods, laboratories and cancer populations has recently been successfully performed for several carcinomas, including bladder cancer. Application of advanced bioinformatics to identify interrelated pathways has revealed common signatures predictive of molecular subgroups, improving histopathological diagnosis, and ultimately outcome prediction. With breast cancer leading the field, colorectal, bladder and renal cell carcinomas well on their way, and many others soon to join, the era of clinical applications of high-throughput molecular methods in cancer lies closely ahead. This review illustrates in detail the perspectives for the management of bladder cancer.

Figure 1

Impact of molecular pathways on molecular cancer diagnosis, example bladder cancer. A: Molecular pathways and malignant development are different dimensions impacting on molecular alterations. If tumors following a certain pathway usually become clinically apparent in an early stage of malignant development (yellow dots), molecular features of this pathway will be associated with a good prognosis. In contrast, “blue” tumors will be associated with a worse prognosis. These patterns are, however, of little help to predict the individual risk of tumors at the same stage of malignant development (red box). Note that pathway characteristics merge and diverge as the disease progresses. The challenge is to distinguish factors leading to “downward” development from those broadening the field. B: illustrates the potential impact of molecular pathway determination as a supplement to histopathology. Papillary structures in preinvasive stages (stage Ta) are easily identified. However, images are not as distinguished in superficial invasive tumors with high grade of dysplasia. Moreover, high‐grade papillary tumors may follow the “CIS‐type” pathway. Identification of a tumor as e.g. “papillary” (=following the papillary pathway) may allow for relevant stratification of molecular alterations into those related to the pathway and those related to malignant development.