The occurrence of two families with three or more affected cases with UCC is extremely rare. There is no evidence that the two families are related. The most likely mode of inheritance in both families is autosomal dominant, with the father in family A possibly dying before symptoms developed. Autosomal recessive inheritance would also be possible in family A and cannot be excluded. Familial TCC is not widely documented; however the few documented familial cases in three families identified in the older literature show much earlier onset of disease than in our families (Fraumeni and Thomas 1967; McCullough et al. 1975; Ilic et al. 2011). Mueller et al. reviewed cases of UCC and identified two cases of later onset UCC with a similar phenotype to our cases (Mueller et al. 2008), with normal testing for HNPCC genes.
DNA has been stored on key siblings for the future identification of candidate genes. So far, no dominantly inherited genes have been implicated in late onset UCC; the interaction between genetic and environmental factors makes their identification challenging. Polymorphisms in genes involved in metabolism of environmental toxins are known to modify individual susceptibility (McCullough et al. 1975).
All the cases we describe have a later onset UCC bladder phenotype. It is unclear whether the other cancers in family B are related or more likely are sporadic occurrences. Urothelial cancers are estimated to occur in up to 18% of MSH2 gene carriers (van der Post et al. 2010; Skeldon et al. 2013), although these are predominantly upper tract TCC rather than bladder although bladder cancers have been reported rarely and with male predominance. Neither of our families had abnormal mismatch repair proteins on immunohistochemistry. Somatic mutations have been identified in bladder cancers with around 50–60% of cases showing mutations in FGFR3 (Balbás-Martínez et al. 2013). Other genes including STAG2 on the X-chromosome (Solomon et al. 2013) have been recognised, but no germline mutations as yet identified in a pure bladder cancer phenotype.
Screening
A family history of UCC causes a two-fold increase (Fraumeni and Thomas 1967; McCullough et al. 1975), in the risk of its occurrence among first degree relatives. The risk is less for more distant relatives. The risk is exacerbated by environmental exposures, particularly smoking, and relatives should be made aware of this.
There is no active screening programme at present for such cases. We have advised relatives in these families to watch closely for symptoms of bladder cancer, (e.g. haematuria), and seek urgent medical attention if any symptoms occur. We recommend regular screening cystoscopy every 3 years, from the 5th decade. Haematuria, or other suspicious symptoms, should prompt discussion with a general practitioner and referral for urgent cystoscopy if needed. Careful taking of a family history and testing for mismatch repair protein tumour immunoexpression may help identify or exclude HNPCC as a cause. In both families, the later onset cases had a higher stage of bladder cancer, and the screened siblings were identified at an earlier age and earlier staging. Treatment was not materially different from sporadic cases. Screening of family members may allow earlier detection of bladder cancers at an earlier stage and improve treatment options and success of treatment.
