Abstract
Twin studies suggest a familial aggregation of bladder cancer but elements of this increased familial risk of bladder cancer are not well understood. To characterize familial risk of bladder cancer, we examined the relationship between family history of bladder and other types of cancer among first-degree relatives and risk of bladder cancer in 1,193 bladder cancer cases and 1,418 controls in a large population-based case-control study. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between family history of bladder cancer (defined as at least one first degree family member with bladder cancer or a cancer of any other site). We also evaluated cancer aggregation of specific sites in family members. Participants with a first degree relative with bladder cancer had nearly double the risk of bladder cancer (OR=1.8, 95% CI:1.2, 2.9) as those without a family history of bladder cancer. Risk was increased for having a sibling with bladder cancer (OR=2.6, 95% CI:1.3, 5.3) compared to no siblings with cancer. Bladder cancer risk was elevated when participants reported a first-degree relative with a history of female genital cancer (OR=1.5, 95% CI:1.1, 2.1), melanoma (OR=1.9, 95%CI:1.02, 3.6), and tobacco-associated cancer (OR=1.3, 95% CI:1.06, 1.6). These findings add to evidence of a familial predisposition to bladder cancer. Clarification of the aggregation of bladder cancer in families and with other cancer sites will be of interest as many loci and common polymorphisms related to bladder cancer have yet to be identified in large genomic studies.
Keywords: Bladder Cancer, Family History, Familial Cancer
INTRODUCTION
In the United States (U.S), bladder cancer is the sixth most common cancer, with 80,470 new cases in 2019.1 Incidence rates are higher for men than women and cigarette smoking is the leading risk factor.2 Twin studies have suggested familial aggregation of bladder cancer, with up to 30% attributable to shared heritability (genetic contribution).3, 4 Case-control and family-based studies have estimated that those with a family history of bladder cancer are approximately twice as likely to develop bladder cancer.5–12
Several elements of this increased familial risk for bladder cancer are not well understood. Some epidemiologic studies have implicated higher risks for bladder cancer among different relatives including parents7–9, 12 and siblings (especially brothers).7, 9, 12 Modifying effects on risk have also been noted by female8, 10 and male gender,8–11 by early age at onset of bladder cancer in case patients5, 9, 10 or relatives,6, 8, 9 as well as by smoking status.8–10, 12, 13 The evidence for familial clustering of bladder cancer in the presence of other cancer sites among relatives is also not clear, with evidence for lymphohematopoietic6, 8, prostate, kidney, thyroid, stomach, lung, cervical, endometrial, and brain cancers being most commonly reported.5, 7, 9, 14, 15 Many of these studies, however, have various limitations, particularly a small number of familial cases, limiting the statistical power of the analysis and, in some cases, a lack of detail on history of cigarette smoking to control for confounding.
To further characterize the familial risk of bladder cancer, we used the New England Bladder Cancer Study (NEBCS), a large case-control study with data on smoking and other bladder cancer risk factors. Our purpose was to examine the relationship between family history of bladder and other types of cancer among first-degree relatives and risk of bladder cancer.
METHODS
The NEBCS is a population-based, case-control study that collected data on 2,631 residents of Maine, Vermont, and New Hampshire. Details have been described previously.16 In brief, cases included all patients ages 30 to 79 years with histologically confirmed, newly diagnosed carcinoma of the urinary bladder (including in-situ carcinomas) that had been diagnosed between September 1, 2001 and October 31, 2004. Patients were ascertained through hospital pathology departments and hospital and state cancer registries. We interviewed 1,213 out of 1,878 eligible bladder cancer patients (65%). An expert pathologist (AS) reviewed their initial diagnostic slides to confirm the diagnosis. Twenty participants had no evidence of bladder cancer and were therefore excluded, leaving 1,193 cases for analysis. We randomly selected controls from state Department of Motor Vehicles registries (age 30–64 years) or the Centers for Medicare and Medicaid Services beneficiary records (age 65–79 years). After frequency matching controls to cases by state, gender, and five-year age group at diagnosis, we interviewed 1,418 control subjects (65% of total eligible controls from Department of Motor Vehicles records and 65% of total eligible controls from Centers for Medicare and Medicaid Services records)(See Figure 1 for details). All participants provided written consent. The study protocol was approved by the institutional review board of the National Cancer Institute and at each collaborating state.
We obtained information regarding demographics, family history of cancer, smoking, and occupation by conducting in-person interviews with study participants. Study participants reported history of cancer for up to seven first-degree family members (limited to biologic parents, siblings, and offspring), the age at diagnosis of those cancers, and the specific site of the cancer for each relative. We used the Surveillance, Epidemiology, and End Results Program (SEER) Cause of Death Recode 1969+ definitions of the International Classification of Diseases, Ninth Revision (ICD-9) to code cancer sites (ICD-9 codes 140–172, 174–239, excluding non-melanoma skin cancer (173)). Only cancer sites with at least 10 cases and 10 controls were evaluated.
For our main analysis, we used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between family history of bladder cancer or cancer of other sites and the participant’s bladder cancer risk. We defined family history of bladder cancer as having at least one first degree family member who reported having been diagnosed with bladder cancer and family history of “other cancer” as having at least one first degree relative who reported having been diagnosed with a cancer of any other site (excluding non-melanoma skin cancers, ICD-9 173). The referent category was defined as those who reported no family history of cancer (excluding non-melanoma skin cancers) in their first-degree relatives. We adjusted all models for state of residence (Maine, Vermont, New Hampshire), gender (female, male), age at diagnosis/interview (<55, 55–64, 65–74, ≥75 years), education (< high school, high school graduate, vocational/some college, college graduate/post college), high-risk occupation (defined as those occupations with an odds ratio of at least 1.5 and having at least 10 exposed participants (yes, no, never worked)), smoking status (non-smoker, occasional smoker (smoked more than 100 cigarettes overall but never regularly), former smoker, current smoker), race/ethnicity (non-Hispanic/Latino white, Hispanic/Latino, other), and personal history of cancer one year prior to the date of diagnosis (cases)/interview (controls) (yes, no). Tests for interaction were computed by comparing nested models with and without the cross-product terms based on a likelihood ratio test.
We conducted analyses evaluating the association between the risk of bladder cancer among participants and selected characteristics of first-degree relatives including: number of relatives with any cancer; age at 1st diagnosis of cancer in family member (≤55 years, >55 years); and relationship of family member with cancer to the subject (parent (mother or father), sibling (brother or sister) or, child). The referent for each of these analyses was those who reported no family history of cancer; however, for specific family member analyses, we restricted the referent to those who reported having these family members. We also evaluated the association between bladder cancer risk in participants and family history of cancer, stratified by selected characteristics of participants including: age at 1st diagnosis of cancer in participant (< 55 years, ≥ 55 years), gender of participant (male, female), smoking status of participant (ever smokers, non-smokers), and high-risk occupation of participant (yes, no).
Individual cancer sites in first degree relative were also evaluated as well as for groups of cancers including: 1) tobacco-associated cancers (cancer of the urinary bladder, lip/oral cavity/pharynx, pancreas, larynx, lung/bronchus/trachea, kidney, stomach, colorectal, liver, cervix, acute myeloid leukemia (https://www.cdc.gov/cancer/uscs/public-use/predefined-seer-stat-variables.htm); and 2) all female genital cancers (uterus, cervix, ovary, vagina, vulva, other female genital organs).
All analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC).
RESULTS
Table 1 shows the distribution of selected characteristics among cases and controls. Almost 60% of both cases and controls were 65 or older, the majority were male (cases: 76%; controls: 73%), and almost all reported their race/ethnicity as non-Hispanic, white (92%) which is typical for the Northern New England population. Most study participants had at least one sibling (94%) as well as one child (93%). Cases were more likely to have ever smoked (85%) than controls (67%) and to have ever been employed in a high-risk occupation (54%) compared to controls (32%). Participants with a first degree relative with bladder cancer had nearly double the risk of bladder cancer (OR=1.8, 95% CI: 1.2–2.9) compared to those without a family history of bladder cancer (Table 2). Sensitivity analyses excluding subjects with a personal history of cancer yielded similar results (OR=1.7 95%CI: 1.04–2.8). There was a 30% increased risk of bladder cancer among participants with two or more family members with a history of any cancer (OR=1.3, 95% CI: 1.03, 1.6) compared to those without a family history of cancer. Bladder cancer risk was also increased for those who reported having a sibling with bladder cancer (OR=2.6, 95% CI: 1.3, 5.3) and for those participants who reported having a sibling with other cancer (OR=1.2, 95% CI: 0.99, 1.5). These increased risks were primarily driven by brothers with bladder cancer (OR=2.6, 95% CI: 1.2, 5.7) and by sisters with other cancers (OR=1.3, 95% CI: 1.01, 1.6). No associations were observed for participants who reported having a parent or child with bladder/other cancer.
Table 1.
Distribution of participants (cases and controls) by selected characteristics*
| Characteristics | Cases N = 1,193 |
Controls N = 1,418 |
||
|---|---|---|---|---|
| N | % | N | % | |
| State | ||||
| Maine | 584 | 49.0 | 740 | 52.2 |
| Vermont | 213 | 17.9 | 252 | 17.8 |
| New Hampshire | 396 | 33.2 | 426 | 30.0 |
| Age | ||||
| < 55 years | 190 | 15.9 | 255 | 18.0 |
| 55 – 64 years | 314 | 26.3 | 336 | 23.7 |
| 65 – 74 years | 438 | 36.7 | 544 | 38.4 |
| ≥ 75 years | 251 | 21.0 | 283 | 20.0 |
| Gender | ||||
| Female | 282 | 23.6 | 379 | 26.7 |
| Male | 911 | 76.4 | 1,039 | 73.3 |
| Race/Ethnicity | ||||
| White, non-Hispanic/Latino | 1102 | 92.4 | 1313 | 92.6 |
| Hispanic/Latino, non-white | 23 | 1.9 | 24 | 1.7 |
| Other, non-Hispanic/Latino | 68 | 5.7 | 81 | 5.7 |
| Education level | ||||
| < High school graduate | 257 | 21.5 | 235 | 16.6 |
| High school graduate | 375 | 31.4 | 412 | 29.1 |
| Vocational/ Some college | 270 | 22.6 | 339 | 23.9 |
| ≥ College graduate | 291 | 24.4 | 432 | 30.5 |
| Siblings | ||||
| 0 | 76 | 6.4 | 92 | 6.5 |
| 1 – 2 | 423 | 35.5 | 554 | 39.1 |
| 3 – 4 | 337 | 28.2 | 389 | 27.4 |
| ≥ 5 | 346 | 29.0 | 375 | 26.4 |
| Missing | 11 | 0.9 | 8 | 0.6 |
| Children | ||||
| 0 | 141 | 11.8 | 185 | 13.0 |
| 1 – 2 | 434 | 36.4 | 536 | 37.8 |
| 3 – 4 | 427 | 35.8 | 519 | 36.6 |
| ≥ 5 | 191 | 16.0 | 176 | 12.4 |
| Missing | 0 | 0.0 | 2 | 0.1 |
| Personal history of cancer | ||||
| No | 986 | 82.6 | 1239 | 87.4 |
| Yes | 207 | 17.4 | 179 | 12.6 |
| Smoking status | ||||
| Non-smoker | 175 | 14.7 | 472 | 33.3 |
| Occasional smoker | 22 | 1.8 | 40 | 2.8 |
| Former smoker | 616 | 51.6 | 699 | 49.3 |
| Current smoker | 379 | 31.8 | 206 | 14.5 |
| High risk occupation** | ||||
| No | 533 | 44.7 | 955 | 67.3 |
| Yes | 649 | 54.4 | 453 | 31.9 |
| Never worked | 11 | 0.9 | 10 | 0.7 |
Some frequencies do not add to total due to missing values
High risk occupations are those with an odds ratio of at least 1.5 and at least 10 exposed participants
Table 2.
Odds ratio (OR) and 95% confidence intervals (CI) for the association between selected characteristics of 1st degree relatives and bladder cancer risk among participants
| Characteristics of 1st degree relatives | Cases | Controls | OR* | 95% CI | ||
|---|---|---|---|---|---|---|
| n | % | n | % | |||
| Type of cancer | ||||||
| None | 451 | 37.8 | 611 | 43.1 | Ref. | Ref. |
| Bladder cancer | 56 | 4.7 | 41 | 2.9 | 1.8 | (1.2, 2.9) |
| Other cancer | 686 | 57.5 | 766 | 54.0 | 1.2 | (0.99, 1.4) |
| Number of relatives with any cancer | ||||||
| None | 451 | 37.8 | 611 | 43.1 | Ref. | Ref. |
| 1 family member | 451 | 37.8 | 515 | 36.3 | 1.2 | (0.96, 1.4) |
| ≥ 2 family members | 291 | 24.4 | 292 | 20.6 | 1.3 | (1.03, 1.6) |
| Age at diagnosis of 1st cancer in family member | ||||||
| None | 451 | 37.8 | 611 | 43.1 | Ref. | Ref. |
| ≤ 55 years | 314 | 26.3 | 332 | 23.4 | 1.2 | (0.98, 1.5) |
| > 55 years | 418 | 35.0 | 467 | 32.9 | 1.2 | (0.99, 1.5) |
| Missing age | 10 | 0.8 | 8 | 0.6 | 1.2 | (0.5, 3.4) |
| Specific member with cancer diagnosis | ||||||
| No parent with cancer | 671 | 56.2 | 835 | 58.9 | Ref. | Ref. |
| Parent with bladder cancer | 29 | 2.4 | 27 | 1.9 | 1.3 | (0.7, 2.3) |
| Parent with other cancer | 493 | 41.3 | 556 | 39.2 | 1.1 | (0.93, 1.3) |
| No mother with cancer | 888 | 74.4 | 1072 | 75.6 | Ref. | Ref. |
| Mother with bladder cancer | 9 | 0.8 | 13 | 0.9 | 0.8 | (0.3, 1.9) |
| Mother with other cancer | 296 | 24.8 | 333 | 23.5 | 1.1 | (0.87, 1.3) |
| No father with cancer | 899 | 75.4 | 1097 | 77.4 | Ref. | Ref. |
| Father with bladder cancer | 20 | 1.7 | 14 | 1.0 | 1.8 | (0.8, 3.7) |
| Father with other cancer | 274 | 23.0 | 307 | 21.7 | 1.1 | (0.89, 1.3) |
| No sibling with cancer | 445 | 37.3 | 542 | 38.2 | Ref. | Ref. |
| Sibling with bladder cancer | 27 | 2.3 | 14 | 1.0 | 2.6 | (1.3, 5.3) |
| Sibling with other cancer | 337 | 28.2 | 355 | 25.0 | 1.2 | (0.99, 1.5) |
| No sister with cancer | 695 | 58.3 | 843 | 59.4 | Ref. | Ref. |
| Sister with bladder cancer | 4 | 0.3 | 3 | 0.2 | 1.6 | (0.3, 7.8) |
| Sister with other cancer | 201 | 16.8 | 205 | 14.5 | 1.3 | (1.01, 1.6) |
| No brother with cancer | 727 | 60.9 | 874 | 61.6 | Ref. | Ref. |
| Brother with bladder cancer | 23 | 1.9 | 11 | 0.8 | 2.6 | (1.2, 5.7) |
| Brother with other cancer | 184 | 15.4 | 201 | 14.2 | 1.0 | (0.8, 1.3) |
| No child with cancer | 991 | 83.1 | 1175 | 82.9 | Ref. | Ref. |
| Child with bladder cancer | 2 | 0.2 | 0 | 0.0 | -- | -- |
| Child with other cancer | 59 | 4.9 | 56 | 3.9 | 1.1 | (0.8, 1.7) |
Adjusted for state, age group, gender, race/ethnicity, smoking status, high risk occupation, personal history of cancer
High risk occupations are those with an odds ratio of at least 1.5 and at least 10 exposed participants
After stratifying on the major risk factors for bladder cancer, there was a suggestion that age at diagnosis among cases could modify risk (p-interaction=0.07); among those younger than 55, there was an increased risk of bladder cancer for those with a family history of bladder (OR=5.2, 95% CI: 1.5, 17.8; however, numbers were small: 10 cases, 5 controls) and other cancers (OR=1.7, 95% CI: 1.1, 2.6), while there were no significant risks observed among those greater than or equal to 55 years of age (Table 3). Among ever smokers, there was an increased risk of bladder cancer for those with a family history of bladder (OR=2.1, 95% CI: 1.2, 3.6) while little or no increased risk was apparent among never smokers (OR=1.3, 95% CI: 0.5, 3.2); the p-value for interaction, however, was not significant (p-interaction=0.33). No other factor (gender or high-risk occupation) appeared to modify the association between family history of bladder cancer (or other cancer) in first degree relatives and bladder cancer risk.
Table 3.
Odds ratio (OR) and 95% confidence intervals (CI) for the association between family history (FH) of cancer and bladder cancer risk, stratified by selected characteristics of participants
| Family history of cancer, stratified by selected characteristics of participants | Cases | Controls | OR | 95% CI | p-interaction, FH of bladder cancer | ||
|---|---|---|---|---|---|---|---|
| n | % | n | % | ||||
| Age | 0.07 | ||||||
| < 55 years | |||||||
| No FH of cancer | 72 | 6.0 | 127 | 9.0 | Ref. | Ref. | |
| FH of bladder cancer | 10 | 0.8 | 5 | 0.4 | 5.2 | (1.5, 17.8) | |
| FH of other cancer | 108 | 9.1 | 123 | 8.7 | 1.7 | (1.1, 2.6) | |
| ≥ 55 years | |||||||
| No FH of cancer | 379 | 31.8 | 484 | 34.1 | Ref. | Ref. | |
| FH of bladder cancer | 46 | 3.9 | 36 | 2.5 | 1.5 | (0.93, 2.5) | |
| FH of other cancer | 578 | 48.4 | 643 | 45.3 | 1.1 | (0.90, 1.3) | |
| Gender | 0.98 | ||||||
| Male | |||||||
| No FH of cancer | 357 | 29.9 | 465 | 32.8 | Ref. | Ref. | |
| FH of bladder cancer | 41 | 3.4 | 26 | 1.8 | 1.9 | (1.1, 3.2) | |
| FH of other cancer | 513 | 43.0 | 548 | 38.6 | 1.2 | (0.96, 1.4) | |
| Female | |||||||
| No FH of cancer | 94 | 7.9 | 146 | 10.3 | Ref. | Ref. | |
| FH of bladder cancer | 15 | 1.3 | 15 | 1.1 | 1.8 | (0.7, 4.2) | |
| FH of other cancer | 173 | 14.5 | 218 | 15.4 | 1.2 | (0.8, 1.7) | |
| Smoking status | 0.33 | ||||||
| Smokers | |||||||
| No FH of cancer | 385 | 32.3 | 397 | 28.0 | Ref. | Ref. | |
| FH of bladder cancer | 47 | 3.9 | 22 | 1.6 | 2.1 | (1.2, 3.6) | |
| FH of other cancer | 585 | 49.0 | 526 | 37.1 | 1.1 | (0.91, 1.3) | |
| Never smokers | |||||||
| No FH of cancer | 65 | 5.4 | 213 | 15.0 | Ref. | Ref. | |
| FH of bladder cancer | 9 | 0.8 | 19 | 1.3 | 1.3 | (0.5, 3.2) | |
| FH of other cancer | 101 | 8.5 | 240 | 16.9 | 1.5 | (1.01, 2.2) | |
| Occupational risk | 0.97 | ||||||
| High-risk occupation** | |||||||
| No FH of cancer | 336 | 28.2 | 419 | 29.5 | Ref. | Ref. | |
| FH of bladder cancer | 37 | 3.1 | 20 | 1.4 | 1.8 | (0.9, 3.5) | |
| FH of other cancer | 524 | 43.9 | 497 | 35.0 | 1.2 | (0.9, 1.5) | |
| No high-risk occupation** | |||||||
| No FH of cancer | 111 | 9.3 | 187 | 13.2 | Ref. | Ref. | |
| FH of bladder cancer | 19 | 1.6 | 21 | 1.5 | 1.9 | (0.99, 3.5) | |
| FH of other cancer | 155 | 13.0 | 264 | 18.6 | 1.2 | (0.9, 1.5) | |
Adjusted for state, age group, gender, race/ethnicity, smoking status, high risk occupation, personal history of cancer, except in the case where stratified on that variable
High risk occupations are those with an odds ratio of at least 1.5 and at least 10 exposed participants
Bladder cancer risk was elevated when participants reported a first-degree relative with a history of any cancer (OR=1.2, 95% CI: 1.01, 1.4), uterine cancer (OR=1.9, 95% CI: 1.1, 3.1), melanoma (OR=1.9, 95% CI: 1.02, 3.6), tobacco-associated cancers (1.3, 95% CI=1.06, 1.6), and female genital cancers overall (includes uterus, cervix, ovary, vagina, vulva, other female genital organs) (OR=1.5, 95% CI=1.1, 2.1) compared to those participants who reported no family history of cancer (Table 4). Borderline significant, positive bladder cancer risks were observed for first-degree relatives with cervical cancer (OR=1.8, 95% CI=0.98, 3.4). No associations with other cancer sites in first-degree relatives were evident.
Table 4.
Odds ratio (OR) and 95% confidence intervals (CI) for the association between the 1st degree relatives’ specific cancer site and bladder cancer risk among participants*
| Cancer site of 1st degree relatives† | Cases | Controls | OR | 95% CI | ||
|---|---|---|---|---|---|---|
| n | % | n | % | |||
| None** | 451 | 37.8 | 611 | 43.1 | Ref. | Ref. |
| All sites | 739 | 61.9 | 807 | 56.9 | 1.2 | (1.01, 1.4) |
| Lip, oral cavity, pharynx | 38 | 3.2 | 43 | 3.0 | 0.9 | (0.6, 1.5) |
| Esophagus | 11 | 0.9 | 11 | 0.8 | 1.3 | (0.5, 3.2) |
| Stomach | 61 | 5.1 | 56 | 3.9 | 1.4 | (0.91, 2.1) |
| Colorectal | 131 | 11.0 | 150 | 10.6 | 1.2 | (0.93, 1.7) |
| Liver | 32 | 2.7 | 44 | 3.1 | 0.7 | (0.4, 1.2) |
| Pancreas | 30 | 2.5 | 38 | 2.7 | 1.03 | (0.6, 1.7) |
| Lung, bronchus, and trachea | 164 | 13.7 | 166 | 11.7 | 1.2 | (0.95, 1.6) |
| Bone | 37 | 3.1 | 30 | 2.1 | 1.4 | (0.8, 2.4) |
| Female breast | 152 | 12.7 | 173 | 12.2 | 1.2 | (0.89, 1.5) |
| Uterus | 42 | 3.5 | 33 | 2.3 | 1.9 | (1.1, 3.1) |
| Cervix | 30 | 2.5 | 20 | 1.4 | 1.8 | (0.98, 3.4) |
| Ovary | 31 | 2.6 | 33 | 2.3 | 1.3 | (0.8, 2.3) |
| Prostate | 93 | 7.8 | 116 | 8.2 | 1.1 | (0.8, 1.5) |
| Kidney | 31 | 2.6 | 27 | 1.9 | 1.6 | (0.87, 2.8) |
| Brain | 40 | 3.4 | 43 | 3.0 | 1.3 | (0.8, 2.1) |
| Melanoma | 28 | 2.3 | 23 | 1.6 | 1.9 | (1.02, 3.6) |
| Lymphoma | 40 | 3.4 | 42 | 3.0 | 1.3 | (0.8, 2.1) |
| Leukemia | 31 | 2.6 | 59 | 4.2 | 0.7 | (0.4, 1.1) |
| Other | 82 | 6.9 | 80 | 5.6 | 1.3 | (0.91, 1.9) |
| Tobacco-associated sites*** | 470 | 39.4 | 476 | 33.6 | 1.3 | (1.06, 1.6) |
| Female genital cancers**** | 106 | 8.9 | 94 | 6.6 | 1.5 | (1.1, 2.1) |
Cancer sites included: urinary/bladder (188); lip, oral cavity, pharynx (14X); esophagus (150); stomach (151); colorectal (153–154, 159); liver (155); pancreas (157); larynx (161); lung, bronchus, trachea (162, 164, 165); bone (170); female breast (174, 175); uterus (179, 182); cervix (180); ovary (183); prostate (185); kidney (189); brain (191, 192); melanoma (172); lymphoma (202.0, 202.1, 202.2, 202.8, 202.9); myeloma (203.0, 238.6); and leukemia (204.0, 204.1, 202.4, 204.2, 204.8, 204.9, 205.0, 2070, 207.2, 206.0, 205.1, 205.2, 205.3, 205.8, 205.9, 206.1, 206.2, 206.8, 206.9, 208.0, 203.1, 207.1, 207.8, 208.1, 208.2, 208.8, 208.9).
Adjusted for state, age group, gender, race/ethnicity, smoking status, high risk occupation, personal history of cancer
Reference group includes participant with no cancer in 1st degree relatives
Tobacco-associated cancers Include cancer of the urinary bladder, lip/oral cavity/pharynx, pancreas, larynx, lung/bronchus/trachea, kidney, stomach, colorectal, liver, cervix, acute myeloid leukemia (https://www.cdc.gov/cancer/uscs/public-use/predefined-seer-stat-variables.htm)
All female genital cancers include uterus, cervix, ovary, vagina, vulva, other female genital organs.
High risk occupations are those with an odds ratio of at least 1.5 and at least 10 exposed participants
DISCUSSION
Overall, we observed an 80% increased risk of bladder cancer among subjects with a first-degree relative with bladder cancer, consistent with previous investigations. After stratifying on the major risk factors for bladder cancer, there was a suggestion that the association may differ by age at diagnosis. We also observed associations between bladder cancer risk and having two or more family members with a history of cancer, and with having a sibling with cancer. Specific cancer sites among first-degree relatives that were associated with increased risk of bladder cancer included uterine cancer and melanoma, tobacco-associated sites overall and possibly cervical cancer.
The association observed between bladder cancer risk and having a first-degree relative with bladder cancer (OR=1.8, 95% CI: 1.2–2.9) was similar in magnitude to observations in a number of studies conducted in other parts of the U.S. and Europe.5–12 Using data on over 500 families with a history of bladder cancer in at least two family members from the Swedish Family-Cancer Database, Hemminki et al.7 estimated the relative risk (RR) in specific family members and found an RR of 1.78 (95% CI: 1.58–2.01) if a parent had bladder cancer. In our study, we did not observe a strong association between family history of cancer in a parent and subsequent risk of bladder cancer in offspring. This may be due, in part, to differences in smoking rates over time. In fact, analyses of 1st degree relatives’ specific cancer sites and bladder cancer risk among participants in our study showed only a modest preponderance of smoking-related cancer sites in common (tobacco associated sites OR=1.3, see Table 4), suggesting that there may be smoking discordance between relatives in this study; unfortunately, we did not have information on relatives’ smoking histories. Additionally, we may have been underpowered to detect such an association as there were only 29 reports of parental bladder cancer in our study. Most studies examining this topic, however, support a link between parental bladder cancer and risk of bladder cancer in offspring.7–9, 12
Similar to several reports,7, 9, 12 we observed an increased risk of bladder cancer for those who reported having a sibling with cancer; in our study, these increased risks were primarily driven by brothers with bladder cancer and by sisters with other cancers. A higher risk of bladder cancer, particularly among brothers, has been reported previously,7 suggesting shared early-life environmental and/or genetic components. Genome-wide association studies (GWAS) have identified over a dozen novel inherited genetic variants that lead to an increased risk of bladder cancer. These studies have shown that known bladder cancer susceptibility loci explain only about 12% of the familial risk of bladder cancer,17 indicating many loci and common polymorphisms related to bladder cancer have yet to be identified.18 The increased risks reported for sisters with other cancer sites is also intriguing. This finding is primarily driven by sisters with melanoma and with female genital cancers (particularly uterine cancer). These sites have also been implicated in large studies of bladder cancer families.7, 8 Unlike bladder cancer, these cancers are not driven by tobacco smoke, suggesting some shared genetic susceptibility. These tumors are known to be caused by, and show, deficits in DNA repair similar to bladder tumors.19, 20 Lynch syndrome, an autosomal-dominant inherited cancer susceptibility syndrome caused by germline mutations in DNA mismatch repair genes have been shown to lead to an increased risk of uterine cancer. This syndrome is also associated with a higher incidence of upper urinary tract cancer (renal pelvis and ureter), and recent studies have also suggested an increased risk for bladder cancer.21, 22 Thus, it is possible that shared genetic factors influencing DNA repair, possibly related to Lynch-associated genes, influence the development of both uterine and bladder cancer in families; however, this requires further investigation.
The strongest association between risk of bladder cancer and specific cancer sites in relatives is for melanoma. Melanomas and bladder tumors show similar cell-cycle pathway, DNA damage response, and PI3-Kinase pathway alterations23, 24 25 as well as some shared germline genetic susceptibility influencing risk for developing these tumors (on chromosomes 3, 5, 6 and 9).23, 26–28 Both tumors are driven by potent, but different, environmental carcinogens (UV radiation and cigarette smoke),2, 28 suggesting there may be a shared biological response to these exogenous stressors resulting in the development of cancer. Future work should consider additional pleiotropic risk loci for melanoma and bladder cancer for discovery of additional shared genetic susceptibility for these two cancer sites. Only one other study evaluated familial aggregation of melanoma with bladder cancer.7 Increased risk of bladder cancer was observed among people with a sister diagnosed with melanoma (RR=1.82 95% CI: 1.01–3.29).7 In our study, the increased risk of bladder cancer was uniformly observed for all first-degree relatives, not just sisters, with melanoma (data not shown). Reports of familial aggregation with other cancer sites have been equivocal, with some studies observing increased risks associated with relatives with lymphohematopoietic cancers6–8 or tobacco-associated sites (other than bladder).5, 7, 9 We did not find evidence of familial aggregation with leukemia or lymphoma but did observe a modest, significant association with tobacco-associated sites, suggesting a shared environmental component. A borderline significant positive association was also observed for cervical cancer, which does have some shared etiology with bladder cancer, possibly due to tobacco smoke and/or human papilloma virus infection29, 30 and has been reported in one other study.5 Ultimately, more work will be needed to fully clarify other cancer sites associated with familial bladder cancer.
After stratifying on the major risk factors for bladder cancer, we found that none significantly modified the associations. We did observe a stronger association for family history of bladder cancer for participants diagnosed at a younger age (<55 years). Although the number of cases was small, these results are consistent with other case-control and familial registry-based studies that evaluated this association.9, 10, 12 We also observed a stronger association for family history of bladder cancer among ever smoking participants compared to never smokers. Although this interaction was not statistically significant, it is consistent with several studies that reported a stronger effect among ever smokers of cigarettes;9, 10, 12, 13 only one study reported a stronger association among never smokers.8 Some other studies have suggested higher risks in men,11 some higher in women,8, 10 but our data do not support these findings. Finally, based on our detailed data on lifetime occupational history, we were also able to evaluate risks among those who held a high-risk occupation. Only one other study evaluated effect modification by high-risk occupations, and like our study, found no association.10
Our study had many strengths. It is one of the largest case-control studies of family history of bladder cancer to date to be conducted in the U.S. We also collected detailed information from study participants on cigarette smoking characteristics and occupational history and adjusted for these in our analysis. Additional strengths include the use of histologically confirmed incident bladder cancers and the population-based design. There were also limitations. Our study was limited in the ability to account for information on detailed demographic and lifestyle factors for 1st degree relatives, most notably for smoking status. In addition, cancer in first-degree relatives was identified via self-report from study participants, without verification of diagnosis. This is an important consideration in the interpretation of aggregation of bladder cancer with other cancer sites. For example, when we examined the OR for reports of uterine cancer among relatives by participant gender, we found that male participants reported significantly elevated bladder cancer risks, while female participants did not, suggesting possible misclassification of reporting by male participants of uterine cancer among their first degree relatives. In contrast, uniform risks were observed for cervical cancer. Our results, however, for uterine and other cancer sites, agree with the results of registry-based family studies where confirmation of cancer in relatives was possible.5, 7, 8
In conclusion, this study supports a positive familial predisposition to bladder cancer. Clarification of the aggregation of bladder cancer with other cancer sites will be of interest in the future as these clues may provide additional avenues for large genomic studies to identify the genetic components of shared heritability of elevated risk in families.
Supplementary Material
Supplemental Figure 1. Final analytic sample and reasons for non-response among eligible cases and controls in the New England Bladder Cancer Study.
Novelty and Impact:
Risk of bladder cancer is nearly doubled when people report a first degree relative with bladder cancer. Aggregation of bladder cancer in families and with other cancer sites, including female genital cancers, melanoma and tobacco-associated sites will help provide clues for additional studies to help uncover the genetic basis of bladder cancer.
Funding:
This work was funded by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (ZIA CP010125-24).
Abbreviations:
- (CIs)
confidence intervals
- (FH)
family history
- (ICD-9)
International Classification of Diseases, Ninth Revision
- (NEBCS)
New England Bladder Cancer Study
- (ORs)
Odds ratios
- (SEER)
Surveillance, Epidemiology, and End Results Program
Footnotes
Competing Interest: None declared
Ethics statement: All participants provided written consent. The study protocol was approved by the institutional review board of the National Cancer Institute and at each collaborating state.
Data Availability Statement:
The data that supports the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Figure 1. Final analytic sample and reasons for non-response among eligible cases and controls in the New England Bladder Cancer Study.
Data Availability Statement
The data that supports the findings of this study are available from the corresponding author upon reasonable request.