SEARCH

SEARCH BY CITATION

Keywords:

  • urinary bladder cancer;
  • familial cancer;
  • familial risks;
  • genetic epidemiology

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Male gender and a family history of cancer are established risk factors for urinary bladder neoplasms. This study used the latest update of the Swedish Family-Cancer Database, which includes 42,255 bladder cancer patients, to investigate the sex-specific incidences and types of tumors in relatives of bladder cancer patients. Men with parents or siblings affected by lung cancer did not show an increased risk of bladder neoplasms. Among women, the familial association was restricted to daughters of women with lung cancer. Brothers showed higher risks than the sons of bladder cancer patients. Men older than 54 years were at an increased risk of bladder cancer only if their fathers or siblings were diagnosed after age 65 years. The present data indicated a limited contribution of smoking to the familial clustering of bladder cancer with other neoplasms. The dependence of the relative risks on the type of familial relationship probably reflected a heterogeneous character of familial aggregation. Age-specific results suggested differential risk factors for tumors diagnosed before 50 years of age versus neoplasms detected later in life. The present data may guide the design of forthcoming gene identification studies and the interpretation of the genome-wide association studies that are about to be published. © 2008 Wiley-Liss, Inc.

After prostate cancer, bladder cancer is the most common urologic malignancy worldwide, with ∼330,000 new cases occurring each year.1 In Sweden, 1,747 men were affected by bladder cancer in 2006, with a 2.1% probability of developing the disease before the age of 75 years.2 Females are affected less frequently than men; 558 women were diagnosed in Sweden in 2006 with a cumulative risk of 0.6% by age 75 years. After laryngeal cancer, bladder cancer shows the highest excess of risk for males compared with females in Sweden.2

Tobacco smoking and occupational exposure to aromatic and heterocyclic amines are well established risk factors for bladder cancer, with large sex-differences in exposure.3–9 Approximately 50% of male and 30% of female urinary tract cancers have been ascribed to smoking and about 10% of male bladder cancer has been attributed to occupational exposures.10, 11 Other known environmental risk factors are radiotherapy to the pelvic area, chemotherapy with cyclophosphamide and chronic bladder infections.12 Variants in several genes coding for xenobiotic transforming enzymes such as N-acetyltransferase 2 (NAT2) and glutathione S-transferase M1 (GSTM1) and also polymorphisms in DNA repair genes, seem to modify the susceptibility to bladder cancer.13–18 Family members share genes and exposures to environmental factors that alter cancer susceptibility. Accordingly, individuals with a family history of bladder cancer and other neoplasms such as leukemia, pancreas, kidney and nervous system cancers have been found to be at an increased risk.14, 19

The objective of this article was to examine the clustering of bladder cancer with other tumors in Swedish families. The Swedish Family-Cancer Database has been used before to investigate this question.19 The substantial increase in the number of familial cases (from 65 affected parent-offspring pairs in the previous version to 279 pairs in the current version) permitted to undertake gender-specific analyses. In addition to 8 extra years of follow-up (from 1996 to 2004), the increment of familial cases was due to the increase in the maximum age of the offspring generation, from 67 years in the previous version to 72 years in the updated Database.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The Swedish Family-Cancer Database was created in the middle of the 1990s by linking census information, death notifications and the administrative family register at Statistics Sweden to the Swedish Cancer Registry. The Database includes persons born in Sweden after 1931 with their biological parents, totaling more than 11.5 million persons and more than 1.2 million tumor notifications—for a detailed description of the Database and its last update see references.20, 21 Calculations were restricted to individuals with identified parents and results were based on 3.4 million nuclear families. The Swedish Cancer Registry relies on separate compulsory notifications of cases from clinicians who diagnosed a neoplasm and from pathologists/cytologists. The percentage of histologically or cytologically verified cases of cancer has been close to 100%.2 A 4-digit diagnostic code according to the 7th revision of the International Classification of Diseases (ICD-7) and subsequent ICD classifications are available since 1961. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were used to compare the risk of urinary bladder cancer in offspring and siblings of cancer patients with the risk of urinary bladder cancer in the general offspring population. Individuals were followed up from birth, immigration date or first year of the study (1961), whichever came latest, until diagnosis of any cancer, death, emigration or December 31, 2004, whichever came first. The estimated incidences were adjusted for the covariates age (5 year groups), sex, socioeconomic index (6 groups), region (4 groups) and calendar year (1961–65, 1965–69, …, 2000–4). We have demonstrated before that the adjustment for family size results in very small differences in the estimated familial relative risks.22, 23 Overdispersion is another possible effect of the clustered family structure of the present data and it was accounted for by adjusting the standard errors from Poisson regression by Pearsons' chi-square divided by the degrees of freedom. The adjustment resulted in practically identical CIs. Since the procedure may be particularly sensitive to outlying observations that are expected in our large dataset, we show in the article unadjusted CIs and point out to the possibility of conservative confidence limits because of familial dependence. Gender-specific and age-specific incidence rates of bladder cancer in Sweden were obtained from NORDCAN (www-dep.iarc.fr/NORDCAN/english/frame.asp).24

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The Swedish Family-Cancer Database included 42,255 patients affected by urinary bladder neoplasms. The proportion of cases with an affected parent or sibling was 5.41%. Table I shows the SIRs of urinary bladder tumors among individuals with a family history of cancer. For example, the Database included 62 bladder cancer patients with a parent affected by neoplasms in the upper aerodigestive tract, the corresponding SIR was 1.12 (95% CI 0.87–1.44). Results are only presented for cancer sites where at least 10 affected parent-offspring pairs were identified. The excluded sites where salivary glands (4 cases), anus (6 cases), nose and nasal sinuses (5 cases), testis (5 cases) and bone (4 cases), none showing significant associations unless noted later. The risk of bladder tumors was significantly increased in individuals with siblings (brothers or sisters) affected by stomach cancer (24 siblings pairs, SIR = 1.56, 95% CI 1.04–2.33). We also identified 3 bladder cancer patients who had one parent and one sibling affected by stomach cancer (SIR = 3.52, 95% CI 1.14–10.9). A parental history of cancer was also significantly associated with an increased risk of bladder neoplasms when parents were affected by bladder (SIR = 1.78), thyroid gland (SIR = 1.57) and kidney (SIR = 1.24) neoplasms. In addition to stomach, a sibling history of bladder (SIR = 2.41), larynx (SIR = 2.16), kidney (SIR = 1.56) and endometrium (SIR = 1.51) tumors and of leukemia (SIR = 1.42) resulted in an increased risk of bladder cancer. Individuals with both a mother and a sister affected by endometrial (SIR = 11.8) or ovarian (SIR = 4.52) neoplasms and individuals with both a parent and a sibling affected by thyroid gland (SIR = 23.4) and liver (SIR = 8.49) cancer showed a high relative risk of bladder tumors, but few cases were identified.

Table I. Relative Risks of Urinary Bladder Tumors for Individuals with a Family History of Cancer
Type of cancer in the probandType of proband
ParentSiblingParent and sibling
NRR (95% CI)NRR (95% CI)NRR (95% CI)
  1. Bolding shows that 95% CI do not include 1.0.

Upper aerodigestive tract621.12 (0.87–1.44)140.96 (0.57–1.61)  
Esophagus301.04 (0.72–1.48)61.04 (0.47–2.32)  
Stomach1600.85 (0.73–1.00)241.56 (1.04–2.33)33.52 (1.14–10.9)
Small intestine100.83 (0.45–1.54)71.84 (0.87–3.85)  
Colon2560.98 (0.87–1.12)450.94 (0.70–1.27)  
Rectum1120.89 (0.74–1.07)241.15 (0.77–1.72)11.01 (0.14–7.15)
Liver1231.13 (0.94–1.35)151.35 (0.81–2.24)28.49 (2.12–34.0)
Pancreas1121.00 (0.83–1.21)171.29 (0.80–2.08)  
Larynx211.13 (0.73–1.73)102.16 (1.16–4.02)  
Lung2351.02 (0.90–1.17)611.07 (0.83–1.37)50.82 (0.34–1.97)
Breast3381.04 (0.93–1.16)1851.09 (0.94–1.26)161.56 (0.96–2.55)
Cervix681.02 (0.80–1.29)261.26 (0.86–1.86)14.22 (0.59–30.0)
Endometrium991.17 (0.96–1.43)351.51 (1.08–2.10)111.8 (1.67–84.1)
Ovary791.03 (0.82–1.28)331.07 (0.76–1.51)24.52 (1.13–18.1)
Other female genital221.33 (0.87–2.02)51.24 (0.52–2.99)  
Prostate4941.05 (0.96–1.15)1001.13 (0.93–1.38)100.78 (0.42–1.45)
Kidney1341.24 (1.04–1.47)341.56 (1.11–2.18)11.65 (0.23–11.7)
Urinary bladder2791.78 (1.58–2.01)632.41 (1.70–3.42)42.35 (0.88–6.25)
Melanoma631.10 (0.86–1.41)491.03 (0.78–1.37)21.45 (0.36–5.82)
Skin, squamous cell1220.95 (0.79–1.13)190.92 (0.59–1.45)10.98 (0.14–6.98)
Eye131.49 (0.86–2.56)20.55 (0.14–2.18)  
Nervous system931.20 (0.98–1.47)431.03 (0.76–1.39)10.57 (0.08–4.01)
Thyroid gland351.57 (1.13–2.19)100.62 (0.33–1.15)123.4 (3.29–166)
Endocrine glands420.83 (0.61–1.12)261.23 (0.84–1.81)  
Connective tissue140.65 (0.39–1.11)81.18 (0.59–2.36)  
Hodgkin disease110.75 (0.41–1.35)111.77 (0.98–3.20)  
Non-Hodgkin lymphoma961.07 (0.88–1.31)261.04 (0.71–1.53)  
Myeloma531.01 (0.77–1.32)90.86 (0.45–1.66)  
Leukemia941.03 (0.84–1.26)321.42 (1.00–2.00)11.30 (0.18–9.23)

Figure 1 represents the age-specific incidence rates of bladder cancer in Swedish men and women from year 2000 to 2006. The excess of incidence in males compared with females increased with age. For example, the incidence rate of bladder cancer in the age band 50 to 54 years was 21.8 per 100,000 for males compared with 7.1 for females (rate ratio 3:1). The corresponding ratio for the ages 80–84 years was 271.2/66.1; rate ratio 4:1.

thumbnail image

Figure 1. Gender-specific and age-specific incidence rates of bladder in Sweden from 2000 to 2006.

Download figure to PowerPoint

The difference between male and female bladder cancer in age-specific incidences calls for gender-specific analyses. Table II shows the SIRs of urinary bladder tumors among men with a family history of cancer. The Database included 41 male bladder cancer patients with a father affected by cancer in the upper aerodigestive tract, the corresponding SIR was 1.43 (95% CI 1.05–1.95). The risk of bladder cancer was also increased in brothers of men affected by stomach (16 siblings pairs, SIR = 2.00, 95% CI 1.23–3.27) and laryngeal (SIR = 2.93, 95% CI 1.52–5.63) cancers. We also identified 3 male patients with sisters affected by anal neoplasms (SIR = 3.56, 95% CI 1.15–11.1, data not shown). Men with a brother (SIR = 1.74), a mother (SIR = 1.45) and a sister (SIR = 1.91) affected by kidney cancer were at an increased risk of bladder tumors. The number of patients was also higher than expected among the male offspring and the brothers of bladder cancer patients. Interestingly, the SIR was significantly higher in brothers (SIR = 3.32) than among the offspring of bladder cancer patients (SIR = 1.60, p < 0.001). Men with affected sisters were also at an increased risk, but the risk excess was not statistically significant. A higher risk of urinary bladder cancer was noticed among men with sisters affected by leukemia (SIR = 2.20, 95% CI 1.30–3.72).

Table II. Relative Risks of Urinary Bladder Tumors for Men with a Family History of Cancer
Type of cancer in the probandType of proband
FatherBrotherMotherSister
NRR (95% CI)NRR (95% CI)NRR (95% CI)NRR (95% CI)
  1. Bolding shows that 95% CI do not include 1.0.

Upper aerodigestive tract411.43 (1.05–1.95)91.25 (0.65–2.40)90.65 (0.34–1.24)30.71 (0.23–2.22)
Esophagus191.19 (0.76–1.87)41.15 (0.43–3.08)50.86 (0.36–2.06)  
Stomach850.90 (0.72–1.11)162.00 (1.23–3.27)470.97 (0.73–1.29)51.21 (0.50–2.91)
Small intestine51.18 (0.49–2.84)42.47 (0.93–6.59)30.65 (0.21–2.02)  
Colon890.95 (0.77–1.17)180.99 (0.62–1.57)1071.03 (0.85–1.25)140.81 (0.48–1.37)
Rectum390.75 (0.55–1.03)101.43 (0.77–2.67)430.97 (0.72–1.31)101.21 (0.65–2.24)
Liver381.15 (0.84–1.58)71.78 (0.85–3.73)591.20 (0.93–1.55)30.65 (0.21–2.00)
Pancreas431.01 (0.75–1.36)101.38 (0.74–2.56)410.96 (0.71–1.31)30.56 (0.18–1.73)
Larynx120.96 (0.54–1.69)92.93 (1.52–5.63)    
Lung1210.92 (0.77–1.10)200.85 (0.55–1.32)511.03 (0.78–1.36)271.30 (0.89–1.90)
Breast20.57 (0.14–2.29)  2501.03 (0.90–1.17)1361.05 (0.89–1.24)
Cervix    501.03 (0.78–1.35)181.14 (0.72–1.81)
Endometrium    781.23 (0.98–1.53)231.30 (0.86–1.95)
Ovary    560.97 (0.75–1.27)251.03 (0.69–1.53)
Other female genital    161.28 (0.78–2.09)20.88 (0.22–3.54)
Prostate3791.08 (0.98–1.20)771.19 (0.95–1.49)    
Kidney511.14 (0.86–1.50)191.74 (1.11–2.74)551.45 (1.11–1.90)111.91 (1.06–3.46)
Urinary bladder1461.60 (1.36–1.89)433.32 (2.46–4.49)541.90 (1.45–2.48)101.54 (0.83–2.86)
Melanoma240.99 (0.66–1.48)170.94 (0.58–1.51)271.25 (0.86–1.83)180.91 (0.57–1.44)
Skin, squamous cell581.01 (0.78–1.31)111.00 (0.56–1.81)411.05 (0.77–1.43)71.44 (0.68–3.01)
Eye40.97 (0.36–2.57)  20.50 (0.12–1.98)10.96 (0.14–6.83)
Nervous system281.21 (0.84–1.76)140.93 (0.55–1.56)371.11 (0.80–1.53)160.98 (0.60–1.60)
Thyroid gland81.60 (0.80–3.20)30.43 (0.14–1.32)181.54 (0.97–2.45)70.94 (0.45–1.98)
Endocrine glands60.84 (0.38–1.86)81.19 (0.60–2.39)230.78 (0.52–1.18)121.18 (0.67–2.09)
Connective tissue70.84 (0.40–1.76)32.52 (0.81–7.81)50.72 (0.30–1.72)41.62 (0.61–4.32)
Hodgkin disease60.89 (0.40–1.98)72.07 (0.99–4.35)  32.57 (0.83–7.97)
Non-Hodgkin lymphoma431.22 (0.91–1.65)90.60 (0.31–1.16)351.11 (0.80–1.55)91.09 (0.57–2.09)
Myeloma231.10 (0.73–1.66)61.29 (0.58–2.87)211.13 (0.73–1.73)20.42 (0.11–1.70)
Leukemia401.01 (0.74–1.39)90.78 (0.41–1.51)230.72 (0.48–1.09)142.20 (1.30–3.72)

The lower incidence of bladder tumors in women compared with men is the cause of the lower number of cases in Table III, which shows SIRs among women with a family history. The highest risk was found in sisters of women affected by pancreatic cancer (SIR = 5.90, 95% CI 2.21–15.7), but only 4 pairs of sisters were identified. Focusing on associations with more than 10 observed cases, increased risks of bladder neoplasms were noticed in daughters of fathers affected by bladder (SIR = 2.07, 95% CI 1.60–2.69) and by nervous system (SIR = 1.94, 95% CI 1.20–3.12) cancers, in daughters of mothers affected by urinary bladder (SIR = 2.42, 95% CI 1.60–3.65) and lung (SIR = 1.81, 95% CI 1.26–2.62) cancers and in women with a sister affected by endometrial cancer (SIR = 2.13, 95% CI 1.21–3.75) and by melanoma (SIR = 1.82, 95% CI 1.01–3.29). We additionally identified 4 mother–daughter pairs where the mother was affected by ocular cancer (SIR = 4.36, 95% CI 1.63–11.6).

Table III. Relative Risks of Urinary Bladder Tumors for Women with a Family History of Cancer
Type of cancer in the probandType of proband
FatherBrotherMotherSister
NRR (95% CI)NRR (95% CI)NRR (95% CI)NRR (95% CI)
  1. Bolding shows that 95% CI do not include 1.0.

Upper aerodigestive tract101.12 (0.60–2.08)20.72 (0.18–2.88)20.36 (0.09–1.45)  
Esophagus30.50 (0.16–1.56)21.79 (0.45–7.15)31.89 (0.61–5.86)  
Stomach190.59 (0.38–0.93)21.50 (0.37–6.00)110.76 (0.42–1.38)21.01 (0.25–4.03)
Small intestine21.06 (0.27–4.25)24.22 (1.05–16.9)  12.70 (0.38–19.2)
Colon280.88 (0.61–1.28)81.26 (0.63–2.52)351.02 (0.73–1.43)50.72 (0.30–1.74)
Rectum170.98 (0.61–1.58)20.44 (0.11–1.76)120.93 (0.53–1.64)20.51 (0.13–2.03)
Liver121.07 (0.60–1.88)10.47 (0.07–3.37)140.88 (0.52–1.48)42.23 (0.84–5.94)
Pancreas100.70 (0.38–1.30)  181.30 (0.82–2.07)45.90 (2.21–15.7)
Larynx81.97 (0.98–3.95)10.62 (0.09–4.4)11.59 (0.22–11.3)  
Lung381.01 (0.73–1.39)40.40 (0.15–1.08)291.81 (1.26–2.62)101.53 (0.82–2.84)
Breast11.50 (0.21–10.7)  851.05 (0.85–1.31)491.23 (0.93–1.63)
Cervix    180.99 (0.63–1.58)81.63 (0.81–3.27)
Endometrium    211.01 (0.66–1.56)122.13 (1.21–3.75)
Ovary    231.19 (0.79–1.79)81.20 (0.60–2.41)
Other female genital    61.49 (0.67–3.32)32.24 (0.72–6.96)
Prostate1140.96 (0.79–1.16)230.95 (0.63–1.44)    
Kidney181.22 (0.77–1.94)41.31 (0.49–3.49)111.04 (0.57–1.87)  
Urinary bladder592.07 (1.60–2.69)111.65 (0.91–2.99)232.42 (1.60–3.65)  
Melanoma60.76 (0.34–1.69)61.01 (0.45–2.26)81.19 (0.60–2.39)111.82 (1.01–3.29)
Skin, squamous cell110.63 (0.35–1.14)10.23 (0.03–1.60)120.81 (0.46–1.43)  
Eye32.54 (0.82–7.87)10.89 (0.13–6.32)44.36 (1.63–11.6)  
Nervous system171.94 (1.20–3.12)40.82 (0.31–2.18)110.97 (0.54–1.76)91.59 (0.83–3.06)
Thyroid gland21.00 (0.25–4.02)  71.79 (0.85–3.75)  
Endocrine glands20.79 (0.20–3.17)  111.10 (0.61–1.99)62.21 (0.99–4.92)
Connective tissue10.41 (0.06–2.90)11.11 (0.16–7.90)10.40 (0.06–2.85)  
Hodgkin disease42.00 (0.75–5.33)  10.56 (0.08–4.01)11.81 (0.25–12.8)
Non-Hodgkin lymphoma131.02 (0.59–1.76)41.91 (0.72–5.11)50.46 (0.19–1.12)41.52 (0.57–4.06)
Myeloma50.73 (0.30–1.75)  40.64 (0.24–1.70)11.23 (0.17–8.76)
Leukemia161.49 (0.91–2.44)61.74 (0.78–3.87)161.50 (0.92–2.45)31.55 (0.50–4.8)

Table IV shows the SIRs of familial urinary bladder cancer according to gender and diagnostic age. The analysis of the median age of onset in affected pairs suggested a cut-off of 55 years for index individuals and 65 years for probands. Among men younger than 55 years, the SIR was 1.99 when fathers were diagnosed with urinary bladder cancer before age 65 years and it was 1.44 if fathers were affected at older ages. The SIR of bladder tumors was particularly high for men younger than 55 years with brothers diagnosed before age 65 years (20 cases, SIR = 5.40). Moreover, when the age of the index individuals was restricted to 55 years and the diagnosis age of the probands to 65 years, the SIR was significantly higher for brothers (SIR = 5.40) than for sons of male patients (SIR = 1.99, p < 0.001). Unexpectedly, men older than 54 years were at an increased risk only if their fathers or siblings were diagnosed after age 65 years. Figure 2 shows the contour plots of the relative risks of bladder cancer according to cumulative ages. In agreement with Table IV, the plots suggest 2 different age-specific components of familial clustering. The first component (tumors diagnosed before age 50 years) can be noticed in father–son (Fig. 2a), brother–brother (Fig. 2b) and father–daughter (Fig. 2d) pairs. The second component (diagnosis age 55–65 years) is observed in father–son (Fig. 2a), mother–son (Fig. 2c) and father–daughter (Fig. 2d) pairs.

thumbnail image

Figure 2. Contour plots of the relative risk of urinary bladder tumors for father–son (a), brother–brother (b), mother–son (c) and father–daughter (d) pairs according to cumulative ages.

Download figure to PowerPoint

Table IV. Relative Risks of Urinary Bladder Tumors According to Age and Sex of Individuals and Age and Type of the Probands
Type of individuals (age)Age of the proband
<65 years≥65 years
NRR (95% CI)NRR (95% CI)
  1. Bolding shows that 95% CI do not include 1.0.

Men with affected father    
 (<55 years)191.99 (1.27–3.12)461.44 (1.08–1.93)
 (≥55 years)141.49 (0.88–2.52)671.58 (1.24–2.02)
Men with affected brother    
 (<55 years)205.40 (3.48–8.39)10.86 (0.12–6.09)
 (≥55 years)141.56 (0.92–2.64)83.01 (1.51–6.03)
Men with a affected mother    
 (<55 years)20.50 (0.12–1.98)171.96 (1.22–3.16)
 (≥55 years)123.71 (2.11–6.54)231.68 (1.11–2.53)
Women with affected father    
 (<55 years)82.18 (1.09–4.38)221.85 (1.21–2.83)
 (≥55 years)52.62 (1.09–6.32)241.76 (1.17–2.64)

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The objective of this study was to explore the incidence and types of neoplasms in families of subjects affected by urinary bladder cancer. The inspection of age-specific incidences suggested that male and female bladder cancer may differ in their etiological components, and the size of the updated Swedish Family-Cancer Database permitted to carry out gender-specific analyses. The investigated sources of data were based on national registries of complete coverage, thus minimizing biases because of recall and ascertainment.20, 21 In the Swedish Family-Cancer Database, parents are registered at the time of birth of the child, thus allowing tracking of “biological” parents despite divorce and remarriage. The reliability of cancer data, reported by pathologists, and the nationwide complete coverage of the Database are important advantages of the present study in comparison with the results which rely on interviews or questionnaires. The study was limited by the fact that the maximum age in the offspring generation was 72 years, still below the age of highest risk for urinary bladder cancer. Unfortunately, information on disease grade and smoking data were not available. Close to 90% of the reported histologies were transitional cell carcinomas whereby analysis by other histological types was not feasible. The number of affected pairs was small for some combinations of cancer types and age categories, and chance because of multiple comparisons probably explains some of the detected associations.

Among men, the highest SIR was related to a sister history of anal cancer. Increased risks were also observed when particular relatives were affected by upper aerodigestive tract, stomach, larynx, kidney and bladder cancers and by leukemia. These types of cancer have been associated with smoking,3 but men with close relatives affected by lung cancer did not show an increased risk of bladder cancer. Among women, the highest risk was found in sisters of women with pancreatic cancer. The anticipated association between lung and bladder tumors was limited to daughters of women with lung cancer, probably reflecting a closer sharing of smoking habits by mother–daughter pairs than by fathers and their offspring.14 Cigarette smoking is the most important risk factor for bladder cancer and no final conclusion can be drawn without adjusting the analyses for smoking, but the present data seem to reflect a limited contribution of smoking to the familial clustering of bladder neoplasms with other types of tumors. In particular, cigarette smoking has not been related to nervous system cancer and negative associations have been reported for endometrial cancer and for melanoma,3, 25, 26 but these neoplasms showed an excess in determined Swedish families. Simulation studies show that, even for lung cancer, no more than 20% of the familial risk can be attributed to smoking.27

Another important result was the dependence of SIRs on the gender and type of familial relationship. For example, the association with hematopoietic malignancies (leukemia), reported in 2 independent studies previously,28, 29 was restricted to men with a sororal history. Only sisters of women with pancreatic cancer showed an increased risk of bladder cancer. Men with mothers or siblings affected by kidney cancer were at an increased risk of bladder cancer, but no association emerged for sons of affected fathers. In summary, with the exception of bladder cancer, familial associations only came out for specific types of familial relationships, thus probably reflecting a heterogeneous etiology of familial bladder cancer. Mutations in DNA repair genes (XRCC3) and variants in genes coding for xenobiotic transforming enzymes (NAT2, GSTM1, GSTP1 and NQO1) have been shown to modify the susceptibility to bladder cancer.13–16, 30–32 These variants are relatively common in Europeans, but the low penetrance conferred by the risk alleles (genotype relative risks between 1.2 and 1.5) result in a limited contribution of these genes to the familial aggregation of bladder cancer.33

The higher familial risks for women compared with men and the higher familial risks when mothers instead of fathers were affected, probably reflected the lower smoking prevalence among Swedish females.34 The higher risks for brothers than for the offspring of bladder cancer patients reported previously was replicated in the present study.14, 19, 35 In particular, the present data indicated that the risk difference was particularly important for men younger than 55 years with relatives diagnosed before age 65 years (99% risk increase for sons vs. 440% increase in brothers of affected men). Possible reasons for this difference are secular changes in the incidence of bladder cancer and passive exposure to cigarette smoking during childhood, which is shared by siblings but not by parents with their offspring. Another possible reason would be the recessive penetrance of yet unidentified susceptibility variants. If parents are unrelated, the proportion of alleles they share identically by descent with their children is 0.5. Siblings share not only alleles, but also allele-allele combinations. Under recessive penetrance, the excess of genetic sharing among siblings results in higher familial risks for siblings than for the offspring of affected patients.34, 36 Since the risk difference was not apparent when women were involved as index patients or as probands, a recessive-genetic component of early onset bladder cancer can be favored over childhood-environmental or X-linked-genetic factors.

An observation of potential interest in gene identification studies was the unexpected increase in SIR with the proband's age of diagnosis in men older than 55 years. Although the number of cases was small in order to draw definitive conclusions, the relationship was observed in both sons and brothers and it suggested a within-family similarity in the age of onset of bladder cancer. In the light of our experience with other types of common tumors, this pattern of familial risk seems to be unique for bladder cancer. The contour plots for selected pairs of individuals supported the hypothesis that tumors diagnosed before age 50 years, and neoplasms identified after this age, are related to different risk factors.

In conclusion, the present data suggest higher risks of early onset bladder cancer for brothers than for sons of affected patients. The higher familial risks in women compared with men could be attributed, in part, to the different smoking prevalences in Sweden in the past decades. Overall, the contribution of smoking and known bladder cancer susceptibility genes to the familial aggregation of bladder cancer with other tumors seems to be relatively modest, although future work is required for an accurate quantification. Interestingly, the familial association between kidney and bladder tumors was repeatedly found in the present study using independent samples of men with affected mothers, brothers and sisters, thus adding consistency to the present data. The familial clustering with other tumors than bladder neoplasms was restricted to specific types of relatives, probably reflecting a complex etiology. The present data may guide the design of forthcoming gene identification studies and the interpretation of the genome-wide association studies that are about to be published.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The Family-Cancer Database was created by linking registers maintained at Statistics Sweden and the Swedish Cancer Registry.

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  • 1
    Ferlay J,Pisani P,Parkin DM. GLOBOCAN 2002: cancer incidence, mortality and prevalence worldwide. Lyon: IARC, 2004.
  • 2
    National Board of Health and Welfare.Cancer incidence in Sweden, 2006, www.socialstyrelsen.se/en/2007.
  • 3
    IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004; 83: 11438.
  • 4
    Brennan P,Bogillot O,Cordier S,Greiser E,Schill W,Vineis P,Lopez-Abente G,Tzonou A,Chang-Claude J,Bolm-Audorff U,Jockel KH,Donato F, et al. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies. Int J Cancer 2000; 86: 28994.
  • 5
    Brennan P,Bogillot O,Greiser E,Chang-Claude J,Wahrendorf J,Cordier S,Jockel KH,Lopez-Abente G,Tzonou A,Vineis P,Donato F,Hours M, et al. The contribution of cigarette smoking to bladder cancer in women (pooled European data). Cancer Causes Control 2001; 12: 4117.
  • 6
    Gandini S,Botteri E,Iodice S,Boniol M,Lowenfels AB,Maisonneuve P,Boyle P. Tobacco smoking and cancer: a meta-analysis. Int J Cancer 2008; 122: 15564.
  • 7
    IARC. Tobacco smoking: monographs on the evaluation of carcinogenic risk of chemicals to. humans, vol. 38. Lyon, France: International Agency for Research on Cancer, 1986.
  • 8
    Nordlund LA,Carstensen JM,Pershagen G. Cancer incidence in female smokers: a 26-year follow-up. Int J Cancer 1997; 73: 6258.
  • 9
    Steineck G,Norell SE,Feychting M. Diet, tobacco and urothelial cancer. A 14-year follow-up of 16,477 subjects. Acta Oncol 1988; 27: 3237.
  • 10
    Zeegers MP,Kellen E,Buntinx F,van den Brandt PA. The association between smoking, beverage consumption, diet and bladder cancer: a systematic literature review. World J Urol 2004; 21: 392401.
  • 11
    Boffetta P,Kogevinas M. Introduction: epidemiologic research and prevention of occupational cancer in Europe. Environ Health Perspect 1999; 107 ( Suppl 2): 22931.
  • 12
    Murta-Nascimento C,Schmitz-Drager BJ,Zeegers MP,Steineck G,Kogevinas M,Real FX,Malats N. Epidemiology of urinary bladder cancer: from tumor development to patient's death. World J Urol 2007; 25: 28595.
  • 13
    Sanderson S,Salanti G,Higgins J. Joint effects of the N-acetyltransferase 1 and 2 (NAT1 and NAT2) genes and smoking on bladder carcinogenesis: a literature-based systematic HuGE review and evidence synthesis. Am J Epidemiol 2007; 166: 74151.
  • 14
    Murta-Nascimento C,Silverman DT,Kogevinas M,Garcia-Closas M,Rothman N,Tardon A,Garcia-Closas R,Serra C,Carrato A,Villanueva C,Dosemeci M,Real FX, et al. Risk of bladder cancer associated with family history of cancer: do low-penetrance polymorphisms account for the increase in risk? Cancer Epidemiol Biomarkers Prev 2007; 16: 1595600.
  • 15
    Kellen E,Hemelt M,Broberg K,Golka K,Kristensen VN,Hung RJ,Matullo G,Mittal RD,Porru S,Povey A,Schulz WA,Shen J, et al. Pooled analysis and meta-analysis of the glutathione S-transferase P1 Ile 105Val polymorphism and bladder cancer: a HuGE-GSEC review. Am J Epidemiol 2007; 165: 122130.
  • 16
    Garcia-Closas M,Malats N,Silverman D,Dosemeci M,Kogevinas M,Hein DW,Tardon A,Serra C,Carrato A,Garcia-Closas R,Lloreta J,Castano-Vinyals G, 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: 64959.
  • 17
    Andrew AS,Karagas MR,Nelson HH,Guarrera S,Polidoro S,Gamberini S,Sacerdote C,Moore JH,Kelsey KT,Demidenko E,Vineis P,Matullo G. DNA repair polymorphisms modify bladder cancer risk: a multi-factor analytic strategy. Hum Hered 2008; 65: 10518.
  • 18
    Wu X,Lin X,Dinney CP,Gu J,Grossman HB. Genetic polymorphism in bladder cancer. Front Biosci 2007; 12: 192213.
  • 19
    Plna K,Hemminki K. Familial bladder cancer in the National Swedish Family Cancer Database. J Urol 2001; 166: 212933.
  • 20
    Hemminki K,Granstrom C,Sundquist J,Lorenzo Bermejo J. The nation-wide Swedish Family-Cancer Database used to assess familial risks of prostate cancer during rapidly increasing incidence. Hered Cancer Clin Pract 2006; 4: 18692.
  • 21
    Hemminki K,Li X,Plna K,Granstrom C,Vaittinen P. The nation-wide Swedish family-cancer database—updated structure and familial rates. Acta Oncol 2001; 40: 7727.
  • 22
    Lorenzo Bermejo J,Hemminki K. Familial risk of cancer shortly after diagnosis of the first familial tumor. J Natl Cancer Inst 2005; 97: 15759.
  • 23
    Lorenzo Bermejo J,Hemminki K. Re: Risks of cancer and families. J Natl Cancer Inst 2006; 98: 5634; author reply 564.
  • 24
    Engholm GS,Storm HH,Ferlay J,Christensen N,Bray F,Olafsdottir E,Pukkala E,Talbäck M. NORDCAN: Cancer incidence and mortality in the Nordic countries, Version 3.0. Copenhagen: Association of Nordic Cancer Registries, Danish Cancer Society, 2007.
  • 25
    Grant W. Smoking, Parkinson's disease and melanoma. Cancer Epidemiol Biomarkers Prev 2007; 16: 2517.
  • 26
    Odenbro A,Gillgren P,Bellocco R,Boffetta P,Hakansson N,Adami J. The risk for cutaneous malignant melanoma, melanoma in situ and intraocular malignant melanoma in relation to tobacco use and body mass index. Br J Dermatol 2007; 156: 99105.
  • 27
    Lorenzo Bermejo J,Hemminki K. Familial lung cancer and aggregation of smoking habits: a simulation of the effect of shared environmental factors on the familial risk of cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 173840.
  • 28
    Aben KK,Witjes JA,Schoenberg MP,Hulsbergen-van de Kaa C,Verbeek AL,Kiemeney LA. Familial aggregation of urothelial cell carcinoma. Int J Cancer 2002; 98: 2748.
  • 29
    Goldgar DE,Easton DF,Cannon-Albright LA,Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 1994; 86: 16008.
  • 30
    Engel LS,Taioli E,Pfeiffer R,Garcia-Closas M,Marcus PM,Lan Q,Boffetta P,Vineis P,Autrup H,Bell DA,Branch RA,Brockmoller J, et al. Pooled analysis and meta-analysis of glutathione S-transferase M1 and bladder cancer: a huge review. Am J Epidemiol 2002; 156: 95109.
  • 31
    Figueroa JD,Malats N,Rothman N,Real FX,Silverman D,Kogevinas M,Chanock S,Yeager M,Welch R,Dosemeci M,Tardon A,Serra C, et al. Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk. Carcinogenesis 2007; 28: 178893.
  • 32
    Chao C,Zhang ZF,Berthiller J,Boffetta P,Hashibe M. NAD(P)H: quinone oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of lung, bladder, and colorectal cancers: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2006; 15: 97987.
  • 33
    Hemminki K,Lorenzo Bermejo J. Constraints for genetic association studies imposed by attributable fraction and familial risk. Carcinogenesis 2007; 28: 64856.
  • 34
    Lorenzo Bermejo J. Gene-environment interactions and familial relative risks. Hum Hered 2008; 66: 1709.
  • 35
    Hemminki K,Sundquist J,Lorenzo Bermejo J. Familial risks for cancer as the basis for evidence-based clinical referral and counseling. Oncologist 2008; 13: 23947.
  • 36
    Burton PR,Tobin MD,Hopper JL. Key concepts in genetic epidemiology. Lancet 2005; 366: 94151.