Urinary cancers may include kidney cancer, ureter cancer, bladder cancer, and two
male cancers, testis and prostate cancers. Epidemiologically, all of them seemed to be
more common in male than female. The knowledge about the genomic effects on their
incidence, prognosis, and responses to chemotherapy or radiotherapy is still very
lacking. As for the ureter and testis cancers, there were almost no genomic studies for
the difficulty of sample collection. Followed are the current SNP literatures about
these cancers in urinary system, and the investigations about ureter and testis cancers
are urgently warrant.
3.7.1. Renal cell carcinoma
Renal cell carcinoma is the third leading cause of death among genitourinary
malignancies and the twelfth leading cause of cancer death overall. The incidence of
renal cell carcinoma is about the figure of 2% worldwide. Due to a widespread use of
abdominal imaging, localized tumors are frequently diagnosed nowadays. However,
roughly one third of the patients will ultimately die from this disease even in USA,
where the healthy caring system is very high-qualified.93
In literature, gender, obesity, smoking, analgesic, diuretic abuse, and
environmental factors are reported to be associated with renal cell carcinoma.83
Cigarette smoking, for example, doubles the risk for renal cell carcinoma and
contributes to as much as one third of all cases, yet only a fraction of smokers and a
low number of nonsmokers develop renal cell carcinoma, which implies influence of
host factors on individual susceptibility.94 These individual differences in
susceptibility to renal cell carcinoma may be attributed to genetic polymorphisms in
DNA repair genes or others.95 In 2008, Margulis and his colleagues have investigated
thirteen SNPs in ten DSB repair genes, including XRCC2, XRCC3, NBS1, BRCA2,
RAG1, ATM, and the four NHEJ genes, XRCC5, XRCC6, ligase 4 and XRCC4.96
The original data showed that the SNPs of XRCC5 rs1805388 and XRCC6 rs132788
were not associated with renal cell carcinoma. However, the XRCC6 rs132788
genotype was considered one of the five critical genotypes determining the overall
renal cell carcinoma risk in the classification and regression tree analysis, with the
most effective NBS1 rs1805794. They concluded that individuals carrying more
putative high-risk genotypes in the DSB repair pathway are at higher risks for renal
cell carcinoma.96
3.7.2. Bladder cancer
Bladder cancer is the most common urinary tumor worldwide. In Europe, bladder
cancer is the fourth most frequent cancer among men, accounting for 7% of total
cancers.97, 98 In USA, bladder cancer is the fifth highest cancer in men and seventh in
women.99, 100 Generally, bladder cancer is three times more common in men than
women, and it is primarily a disease of the elderly, with 80% of the patients in the
50-79-year age group and a peak in the seventieth age. Environmental exposures to
tobacco are the predominant risk factors for bladder cancer. The bladder cancer
incidence is two to three folds higher among cigarette smokers as compared with
non-smokers.101 Occupational exposure to carcinogens, alcohol consumption, dietary
factors and the use of hair dyes have also been suggested as risk factors for bladder
cancer.102-106
Although loss of XRCC5 can result in the genome instability and in initialization
of carcinogenesis, over-expression of XRCC5 is associated with the progression of
bladder cancer.107 The expression of XRCC6 is elevated in bladder tumor tissue107 and
XRCC6 may function as a caretaker gene for the development of T-cell
lymphomas.108 In 2008, Wang and his colleagues have published two papers
investigating the roles of XRCC5109 and XRCC6,110 in bladder cancer in China. In the
former study, a polymorphism with a variable number of tandem repeats (21-bp repeat
elements at the position 201 to 160 bp upstream to the initiation of transcription) in
the XRCC5 was investigated of the association with bladder cancer risk. There are
three different alleles, one includes the 42 nucleotide repeat elements (2R), another
contains only one 21-nucleotide repeat in the rectangular box (1R), and still the other
includes no repeat element (0R). The frequencies of the 2R/2R, 2R/1R, and 2R/0R
genotypes among the cases were less than those for the controls, while the proportions
of the 1R/1R, 1R/0R, and 0R/0R genotypes were greater. Overall the difference of the
genotype distributions between the cases and the controls was significant, and
individuals not carrying the 2R allele had a 1.75-fold increased risk of bladder cancer
compared with those carrying the 2R allele.109 The authors has also measured the
promoter activities of the 2R, 1R and 0R alleles by transient transfection in HeLa, T24,
and NIH3T3 cells, finding that fewer tandem repeats in the XRCC5 promoter
increased the activity of the XRCC5 transcript.109 The later paper investigating the
same population has observed an association between XRCC7 rs7003908, but not
XRCC6 rs2267437, genotype and the bladder cancer risk. Also, the risk is increased
among the elder (>65 years old) smokers, suggesting that a gene-environment
interaction may be involved in the development of bladder cancer.110 It is reported that
2-naphthylamine and 4-aminobiphenyl, the compounds in tobacco smoke, can cause
genetic damage in urothelium,111, 112 which may enhance the cellular proliferation in
bladder carcinogenesis.111, 113 In 2009, Michiels and his colleagues have analyzed the
gene-environment joint effects on bladder cancer risk,114 using the classification and
regression tree method similar to that performed gene-gene interaction by Wu.115
Smoking status and genotype data for up to 652 SNPs were incorporated in the
analysis to explore gene-gene and gene-smoking interactions. The outcome is as
expected, the smoking status is the most critical risk factor for bladder cancer. In ever
smokers, a potential two-order interaction between the two SNPs, XRCC5 rs4674066
and ligase 1 rs2288878 was observed. The results suggested that smoking habits,
XRCC5 CC and ligase 1 CT or TT, are sequentially three determinants for bladder
cancer susceptibility in each subject. Very similar to this finding, Chang and his
colleagues has found that there is a joint effects of XRCC5 genotype and personal
smoking habits on bladder cancer risk in Taiwan.116 In this study, a significant
different distribution was found in the frequency of the XRCC5 rs828907, but not
rs11685387 or rs9288518. In addition, those people carried GT and TT genotype at
rs828907 had a 2.05-fold enhanced risk when they had the habit of tobacco smoking,
but not alcohol consumption.116
3.7.3. Prostate cancer
Prostate cancer, a worldwide male disease, is the leading cause of illness and cancer
death in males.117 In addition to age, race and a family history of prostate cancer,
unbalanced diet, androgens, occupational chemicals, smoking, inflammation and
obesity are considered to be additional secondary risk factors.118 Recently, carbon ion
radiotherapy with an established dose fractionation regimen has been shown to yield
biochemically satisfactory relapse-free rates without local recurrence and with
minimal morbidity.119-121 In 2007 and 2008, Suga and his colleagues investigated the
association between 450 SNPs in 118 candidate genes and radiation susceptibility in
prostate cancer patients after carbon ion radiotherapy.122, 123 The genotype of XRCC6
rs2267437, together with those for other four SNPs, SART1 rs2276015, ID3
rs2742946, EPDR1 rs1376264 and PAH rs1226758, were the determinants for the
prediction of developing dysuria after carbon ion radiotherapy in prostate cancer
patients. Despite the small population recruited, their work has set a very good
example for the evaluation of side effects after clinical therapy, using the patients
from a single hospital without the confounding effects of therapeutic protocols and
differential scoring from various examiners and multiple institutions.123