May 6, 2004 Access past issues

Reviewed by: Shauna Lyn, MD Office of Genomics and Disease Prevention Office of the Director Centers for Disease Control and Prevention

The Health Outcome

Bladder cancer includes both transitional cell carcinoma (most common in North America and Europe ) and bilharzial bladder cancer (associated with squamous cell carcinoma and most common in Northern Africa ). Bladder cancer causes more than 130, 000 deaths annually worldwide (1) . The incidence and mortality of this disease increases directly with age, and is more common in men. Cigarette smoking is the most common exposure to the carcinogenic arylamines that are thought to contribute to bladder cancer , with up to 50% of cases in men and 20% of cases in women being attributed to smoking (2) . Environmental/ occupational exposure to arylamines occurs in the chemical, dye, rubber, and textile industries. Bladder cancer is the fourth most frequent cancer in men in the European union, with 52,000 new cases and 22,000 deaths each year. Italy had the highest incidence rate of bladder cancer in Europe in 2000 (3).

Reduced DNA repair capacity is thought to be a risk factor for cancer. There are four major DNA repair pathways in human cells: nucleotide excision repair (NER), base excision repair (BER), double strand break repair (DBR), and mismatch repair (MMR). A genetic mutation that results in a deficiency at any point along one of these pathways can lead to genetic instability and an increased risk for carcinogenesis. Polymorphisms for different DNA repair genes can slightly alter the structure of DNA repair enzymes and, in turn, modulate cancer susceptibility. Shen, et al examined three such genes and their interactions with environmental exposures commonly associated with bladder cancer (4). XRCC1 (Arg ³⁹⁹Gl) is a component of the base excision repair pathway. It functions as a “scaffolding protein” that fixes base damage and DNA single strand breaks. The amino acid substitution is not known to have functional consequences. XRCC3(Thr ²⁴¹Met) is located at exon 7, which is not known to be a functional domain. It takes part in homologous recombination repair of DNA double strand breaks and cross- links, and interacts directly with Rad51 (a eukaryotic homolog of the bacterial RecA recombinase). XPD(Lys ⁷⁵¹ Gln) functions in the nucleotide excision repair pathway and works as an ATP- dependent helicase. It is necessary for normal transcription initiation and nucleotide excision repair. Mutations may cause defects in DNA repair, transcription, and apoptosis (5-8).

The Finding

Shen, et al reported associations of the above three DNA repair gene polymorphisms with bladder cancer. From July 1997 through December 2000, t hey conducted a hospital- based, case- control study of men in a highly industrialized area of Italy called Brescia . Brescia has one of highest mortality rates from bladder cancer among men in Western Europe (4) . The study included 201 case patients with histologically confirmed bladder cancer and 214 control patients who had non-neoplastic urologic diseases. Subjects were frequency-matched for age (+/- 5 years), period of recruitment, and hospital of admission. A semi-structured questionnaire was used to assess subjects’ environmental exposures to smoking, polycyclic aromatic hydrocarbons (PAHs), and aromatic amines. Genotyping was done using white blood cells extracted from blood samples taken during hospital admission. PCR and enzymatic digestion analysis was used to obtain XRCC1
(Arg ³⁹⁹Gl) , XRCC13(Thr ²⁴¹Met), and XPD (Lys ⁷⁵¹Gln)polymorphisms.

The authors found that both the XRCC1 codon 399 and the XRCC3 codon 241 polymorphisms were protective against bladder cancer, an effect that was most apparent among heavy smokers [OR 0.49 (CI 0.28- 0.88) and OR 0.38 (CI 0.14- 1.02), respectively]. They did not find the XRCC1 polymorphism to be associated with bladder cancer risk [OR 0.92, (CI 0.62- 1.37)]. Effects of the genotypes were estimated using unconditional logistic regression and adjusted for age as a continuous variable. Multivariate ORs and 95% CIs of environmental risk factors were calculated using unconditional logistic regression and adjusted for age, education, residence, and accumulative tobacco consumption. There was no evidence of interaction between any of the three polymorphisms and either tobacco smoking or occupational exposure to PAHs and aromatic amines.

Public Health Implications

Although smoking, PAHs and aromatic amines have long been associated with increased bladder cancer risk, the results of studies that evaluate the relationship between polymorphisms of several DNA repair genes and bladder cancer risk have been inconsistent. Recently, for example, Stern, et al found XRCC1 codon 399 to be protective (2), Matullo, et al found XRCC3 codon 241 to increase bladder cancer risk (9), and Sanyal, et al found no effect of XRCC1, XRCC13, or XPD polymorphisms on bladder cancer risk (10). Likewise, the effects of environmental exposures in relation to these polymorphisms are far from established, and more research is needed. It is hoped that such studies will help to clarify the causes of bladder cancer and which individuals are at highest risk for disease. While rare mutations of DNA repair genes cause lethal genetic disease, it is the more common DNA repair gene polymorphisms that are thought to modulate an individual’s disease susceptibility. As Shen, et al point out, “Although genetic variants of these genes at one or more loci are likely to be associated with only moderate changes in cancer risk, they are prevalent in the population and may contribute to the overall population risk of cancer.” (4)

References

1. Ferlay J, et al. Globocan 2000: cancer incidence, mortality and prevalence worldwide. IARC CancerBase No. 5. Lyon , France : IARC Press; 2001.
2. Stern MC, et al. DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk. Cancer Epidemiology, Biomarkers & Prevention   2001 February;10: 125-131.
3. Black RJ, et al. Cancer incidence and mortality in the European union. Cancer Registry data and estimates of national incidence for 1990. Europ. J Cancer 1997; 33:1075-1107.
4. Shen M, et al. Polymorphisms of the DNA repair genes XRCC1, XRCC3, XPD, interaction with environmental exposures, and bladder cancer risk in a case- control study in northern Italy . Cancer, Epidemiology, Biomarkers & Prevention  2002 November;12: 1234-1240.
5. Goode, EL, et al. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer, Epidemiology, Biomarkers & Prevention  2002 December;11: 1513-1530.
6. McKusick VA , et al. X-ray repair, complementing defective, in Chinese hamster, 1; XRCC1 ; XRCC1. Accessed March 1, 2004 . Website.
7. McKusick VA , et al. X-ray repair, complementing defective, in Chinese Hamster, 3; XRCC3 ; XRCC1. Accessed March 1, 2004 . Website.
8. McKusick VA , et al. Xeroderma Pigmentosum, Complementation Group D; XPD ; XRCC1. Accessed March 1, 2004 . Website.
9. Matullo G, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case- control study. Int J Cancer  2001;92:562- 567.
10. Sanyal S, et al. Polymorphisms in DNA repair and metabolic genes in bladder cancer. Carcinogenesis  2003 December.