Familial And Genetic Risk Of Transitional Cell Carcinoma Of The Urinary Tract

Main Category: Urology / Nephrology
Also Included In: Cancer / Oncology
Article Date: 24 Jul 2008 - 0:00 PDT

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UroToday.com - Bladder cancer is the second most common genitourinary malignancy, and the incidence has continued to rise modestly since 1975. It occurs primarily in middle-aged men, and the majority of newly-diagnosed bladder cancers are low-grade, superficial, transitional cell carcinomas (TCCs). 1 Most urinary tract TCCs originate in the bladder; however, a minority arise in the renal pelvis or ureter, prompting us to use the term "transitional cell carcinoma of the urinary tract" (TCCUT) in our report. Unfortunately, the pathogenesis of TCCUT remains incompletely defined. Investigations of individuals and families at high risk of cancer often lead to etiologic clues to the pathogenesis of disease in the general population, and may help to identify those persons most likely to benefit from screening and risk-reduction programs.

Environmental exposures (e.g., tobacco smoke, aromatic amines) have been clearly implicated as causes of TCCUT, although only a small fraction of individuals exposed to these risk factors actually develop cancer. Polymorphisms in low-penetrance genes (e.g., NAT2, GSTM1) involved in the metabolism of environmental toxins modify individual susceptibility to bladder carcinogens and bladder cancer risk.2,3 Our review of epidemiologic studies revealed that a family history of TCCUT is associated with an approximately two-fold increase in cancer risk that cannot be fully explained by smoking. Furthermore, a hereditary predisposition to bladder cancer is confirmed by its excess occurrence in several Mendelian disorders (e.g., hereditary non-polyposis colorectal cancer (MLH1, MSH2, MSH6, and PMS2), retinoblastoma (RB1), Costello syndrome (HRAS), Apert syndrome (FGFR2) and reports of multiple-case TCCUT families.

Our literature review revealed only 32 reports of multiple-case TCCUT families. Unfortunately, no uniform criteria were used to define familial TCCUT. Therefore, some of these families may not represent valid examples of pure site-specific TCCUT familial aggregations, highlighting the importance of recognizing the strengths and limitations of the criteria used to explore an underlying genetic predisposition to TCCUT.

We evaluated two multiple-case families in our clinical cancer genetics research program, and were not able to correlate the acetylation (NAT2) metabolic phenotype with TCCUT occurrence, suggesting that other genetic variants remain to be identified that impact risk. Previous cytogenetic studies of multiple-case families failed to identify candidate gene locations; and a prior segregation analysis provided no support for a major susceptibility gene, although the latter was inadequately powered to definitively exclude this possibility. Most families reported thus far consist of only two affected family members, likely explaining why linkage analysis of multiple-case families has not been performed.

Ultimately, familial TCCUT is either very uncommon or significantly under-reported, perhaps based on the assumption that TCCUT is unequivocally due to various environmental exposures.

Among all familial TCCUT aggregations, a major gene could account for a site-specific subset. This important question can only be answered by additional studies targeting extended multiple-case families. Our research program is actively considering a major new multidisciplinary research effort aimed at recruiting a large number of multiple-case, site-specific TCCUT families. We initiated a nationwide recruiting campaign, but have thus far identified only 5 new families. We continue to enroll new families: please contact the Clinical Genetics Branch Family Studies Referral Nurse at 1-800-518-8474 to make a referral.

Common low-penetrance genetic factors acting in concert with environmental exposures may also contribute to familial TCCUT. Genome-wide association studies (GWAS) employ 500,000 to 1,000,000 genetic markers in large cohorts, more easily facilitating the identification of novel disease susceptibility loci. This approach has yielded several high-impact, novel genetic loci for various common diseases, both malignant and non-malignant.4 A planned GWAS for urinary bladder cancer may help to clarify the role of the candidate gene pathways reviewed here, as well as to characterize gene/environment interactions that contribute to TCCUT.

1. Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer Statistics, Trends, and Multiple Primary Cancer Analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 2007;12(1):20-37.
2. Silverman DT, Devesa SS, Moore LE, Rothman N. Bladder Cancer, Third ed. New York: Oxford University Press, 2006.
3. Garcia-Closas M, Malats N, Silverman D, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet 2005;366(9486):649-59.
4. Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest 2008 118:1590-605.

Written by
Christine M. Mueller, DO, Neil Caporaso, MD, and Mark H. Greene, MD, as part of Beyond the Abstract on UroToday.com.

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