Familial and genetic risk of transitional cell carcinoma of the urinary tract

Abstract

Environmental exposures, including tobacco smoke and occupational exposure to aromatic amines, have been implicated in bladder cancer etiology. However, the pathogenesis of urinary bladder transitional cell carcinoma remains incompletely defined. In epidemiologic studies, family history confers a two-fold increase in bladder cancer risk, but it is uncertain whether this represents evidence of a genetic and/or a shared environmental basis for familial aggregation. Polymorphisms in genes involved in the metabolism of environmental toxins (e.g., NAT2) clearly modify individual susceptibility to bladder cancer. A genetic predisposition has also been suggested by case reports describing multiple-case families, and the development of bladder cancer in association with several well-described Mendelian disorders (e.g., HNPCC, retinoblastoma). Here we update a previouslyreported family, report a new multiple-case kindred, critically review previously-reported bladder cancer families and the epidemiologic literature related to family history of transitional cell carcinoma of the urinary tract (TCCUT) as a risk factor, as well as provide a brief summary of genetic factors that have been implicated in TCCUT risk. We conclude that familial TCCUT is either very uncommon or significantly under-reported, perhaps on the assumption that this is an environmental rather than a genetic disorder. The interaction between multiple genetic and environmental factors has made it challenging to identify genetic components responsible for many common diseases; therefore, a proposed genome-wide association study (GWAS) for urinary bladder cancer may help to clarify the etiologic role of the candidate genetic pathways reviewed here, as well as characterize gene/environment interactions that contribute to TCCUT carcinogenesis.

Unique clinicopathologic and molecular characteristics of urinary bladder tumors in children and young adults

“…Upper tract urothelial neoplasms reportedly occur at a higher incidence and at slightly younger median age of onset (56 years) [21,22] in this group of patients than otherwise expected. Evidence of increased risk of urothelial neoplasia in the bladder in these patients is less compelling [21,22], and currently there is no evidence of increased risk of urothelial neoplasia in pediatric patients with HNPCC syndrome, as noted by Wild et al in their study of urothelial neoplasms in patients under age 20 years [6]. In the same patient group, no familial bladder cancer history was identified [3].…”

“…However, even in the absence of such treatment, increased mortality from bladder cancer in comparison to the general population has been noted, suggesting that it may indeed be a component of the hereditary retinoblastoma spectrum [22].…”

“…Bladder cancer is sometimes a component of Costello syndrome, a rare autosomal dominant disorder in which patients are at risk for various malignancies such as rhabdomyosarcoma, neuroblastoma, and urinary bladder UC [22,23]. These patients have been reported to develop papillary UC during childhood [23,24], sometimes with recurrence, suggesting that hematuria or other urinary tract symptoms in patients with Costello syndrome should prompt consideration of a bladder tumor work-up [24].…”

Papillary Urothelial Neoplasm of Low Malignant Potential: A Case Report

“…Possible genetic link for PUNLMP in young cases has been observed but overlapping with environmental risk factors makes it difficult to provide a definitive conclusion. [4] PUNLMPs have variable and increased incidence of rate of recurrence (10-45%) & progression (0-29%). [5,6] These patients should be monitored regularly for recurrence or progression.…”

Constitutional and occupational risk factors associated with bladder cancer

“…We briefly describe the most important. [15][16][17][18][19][20] Hereditary nonpolyposis colorectal cancer syndrome: Caused by germline mutations in MLH1, MSH2, MSH6 and PMS2 mismatch repair genes. The predominant locations of urothelial cancers are renal pelvis and ureter; the vesical locations are less common.…”