Genetic Predisposition to Bladder Cancer

Cancer may be caused by a combination of factors, including random mutations introduced during cell division, mutations caused by extrinsic lifestyle or environmental exposures (see Chap. 1 ), or intrinsic characteristics that speed up or slow down the mutational processes. One of the most important intrinsic characteristics is aging, which causes (1) decreased efficiency of DNA repair mechanisms, (2) accumulation of DNA errors in cells, (3) conversion of protective mechanisms in early life (such as senescence) into risk factors later in life (i.e., antagonistic pleiotropy), and (4) immune senescence. The other important characteristic is germline DNA variation which can prevent or support the initiation and promotion of somatic mutagenesis through variation in several pathways such as DNA repair, immune response, detoxification of carcinogens, or susceptibility to risk factors such as smoking, alcohol, or obesity. It is estimated that 5–10% of all cancers are caused by a strong genetic predisposition in which high-penetrance rare alleles in a single or few genes affect susceptibility. Usually, such a strong predisposition can be suspected based on the familial clustering of cancers. Clinical geneticists frequently consult families on the risk of breast, ovarian, colorectal, and many other cancers. This is not the case for bladder cancer (BC), for which familial clustering due to high-penetrance germline mutations is extremely rare. However, lower-penetrance germline DNA variations play an important role. Many such variants have been discovered through genome-wide association studies (GWAS) using high-resolution genome-wide DNA variation chips and imputation. This has also been augmented by targeted sequencing of panels of higher-penetrance candidate genes (see Fig. 2.2). Meta-analyses of multiple GWAS and targeted studies help to refine the map of low-penetrance DNA variation. Ongoing efforts aim to identify genetic variation that influences BC prognosis directly or through modification of treatment effects. This chapter will summarize the evidence on the genetic predisposition of BC and BC prognosis, from early case reports to recent sequencing studies.