Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case–Control Study

Abstract

Background

Family history of bladder cancer confers an increased risk for concordant and discordant cancers in relatives. However, previous studies investigating this relationship lack any correction for smoking status of family members. We conducted a population-based study of cancer risks in relatives of bladder cancer patients and matched controls with exclusion of variant subtypes to improve the understanding of familial cancer clustering.

Methods

Case subjects with urothelial carcinoma were identified using the Utah Cancer Registry and matched 1:5 to cancer-free controls from the Utah Population Database. Cox regression was used to determine the risk of cancer in first-degree relatives, second-degree relatives, first cousins, and spouses. A total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed. To correct for smoking status, we performed a secondary analysis excluding families with elevated rates of smoking-related cancers. All statistical tests were two-sided.

Results

First- and second-degree relatives of case subjects had an increased risk for any cancer diagnosis (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 1.03 to 1.09, P < .001; HR = 1.04, 95% CI = 1.02 to 1.07, P = .001) and urothelial cancer (HR = 1.73, 95% CI = 1.50 to 1.99, P < .001; HR = 1.35, 95% CI = 1.21 to 1.51, P < .001). Site-specific analysis found increased risk for bladder (HR = 1.69, 95% CI = 1.47 to 1.95, P < .001), kidney (HR = 1.30, 95% CI = 1.08 to 1.57, P = .006), cervical (HR = 1.25, 95% CI = 1.06 to 1.49, P = .01), and lung cancer (HR = 1.34, 95% CI = 1.19 to 1.51, P < .001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR = 1.35, 95% CI = 1.2 to 1.5, P < .001) and thyroid cancer (HR = 1.18, 95% CI = 1.03 to 1.35, P = .02). Spouses showed an increased risk for laryngeal (HR = 2.68, 95% CI = 1.02 to 7.05, P = .04) and cervical cancer (HR = 1.57, 95% CI = 1.13 to 2.17, P = .007). These results did not substantively change after correction for suspected smoking behaviors.

Conclusion

Our results suggest familial urothelial cancer clustering independent of smoking, with increased risk in relatives for both concordant and discordant cancers, suggesting shared genetic or environmental roots. Identifying families with statistically significant risks for non-smoking-related urothelial cancer would be extremely informative for genetic linkage studies.

Studies that examine familial aggregation of bladder cancer have suggested that there is a strong familial component to bladder cancer (1–4). For example, brothers of a proband diagnosed before age 45 years have approximately seven times the risk of bladder cancer (1). Closer genetic proximity to the proband and younger age of the proband at the time of diagnosis have been shown to be consistent risk factors for both concordant (bladder) and discordant (nonbladder) cancers in relatives (1–4). However, due to limitations with cohort selection and the failure to adjust for smoking status, these findings are less compelling and the causal factors driving those cancer cluster patterns remain unclear.

One issue with previous studies was the presentation of bladder cancer as a single entity, on the basis of anatomical site, without regard to histology (1–4). However, in terms of epidemiologic and genetic characteristics, urothelial and nonurothelial cancers are distinct. Squamous cell carcinoma, for example, is more likely in females and is most strongly associated with chronic infection or irritation (5). In fact, lower tract urothelial carcinoma may be more closely related to upper tract urothelial carcinoma than other subtypes of bladder cancer; epidemiologically speaking, histology is potentially more important than site (6).

Another important issue affecting the interpretation of these studies was the absence of smoking status identification or correction. In addition to finding increased risk of bladder cancer in relatives, previous cohorts also reported higher risk of lung, thyroid, and kidney cancer, as well as increased overall cancer risk. Cigarette smoking is the most common risk factor for bladder cancer, with both duration (number of years smoking) and frequency (number of packs per day over the number of years smoking) affecting a patient’s risk (7,8). Due to the potential confounding effects of smoking, the primary cause for the increased risk of bladder cancer as well as discordant cancers in relatives is impossible to determine (1–3).

In this study, we present a population-based study of cancer risk in relatives and spouses of urothelial cancer (UCa) patients using data from the Utah Population Database (UPDB). The objective of this study is to better characterize the pattern of familial clustering of cancers by determining the risk of both concordant and discordant cancers in relatives of UCa patients in a population with overall low rates of smoking. Utah has the lowest rate of smoking in the United States, at 9.3% (9). Probands with nonurothelial subtypes of cancer were excluded from this analysis to better characterize the pattern within this subtype. The baseline analyses were performed establishing the baseline risk in relatives. We further identified the role of shared environment using spouses, with an increased cancer risk in this group indicating shared environmental risk. Smoking corrected analyses were performed excluding families with cancer-clustering patterns that are congruent with smoking-related behaviors (determined by Familial Standardized Incidence Risk [FSIR]) (10). Stratified analyses were run to determine if the risk varied by age at diagnosis of the proband. We hypothesized that after we corrected for smoking-related behaviors and limited our analysis to urothelial cancer (UCa), there would be an increased risk of concordant and discordant cancers with closer genetic proximity to the proband and that the risk of UCa in family members would be higher for probands diagnosed at younger ages.

Methods

Study Design and Data

This study utilized the genealogical, demographic, and health history information within the Utah Population Database (UPDB). The UPDB has supported numerous biodemographic, epidemiologic, and genetic studies in large part because of comprehensive population coverages, pedigree complexity, and linkages across data sources (11,12). A population-based, case–control study of Utah residents diagnosed with their first primary lower or upper tract urothelial carcinoma between 1966 and 2014 was used to assess the risk of cancer in family members and spouses of bladder cancer subjects (Probands = 7266). Among case subjects, average age at diagnosis was 72 years. Figure 1 shows a schematic of the sample selection. Cancer-free population controls were selected randomly, without replacement, from the UPDB and matched 5:1 to probands by sex and birth year (n = 36 318). In addition to having genealogy information to determine family relationship in the UPDB, eligible control subjects had no history of UCa and were living in Utah during the period of time that the matched proband was diagnosed with UCa. Family members of case subjects and control subjects were selected from the UPDB. First-degree relatives (FDRs) included parents, children, and siblings (FDR_Probands = 32 604, FDR_Controls = 170 125). Second-degree relatives (SDRs) included grandparents, grandchildren, aunts/uncles, and nieces/nephews (SDR_Probands = 91 925, SDR_Controls = 487 510). Risk in first cousins (FCs; FC_Probands = 100 033, FC_Controls = 516 933) and spouses (Spouse_Probands = 4689, Spouse_Controls = 22 984) of UCa patients was also evaluated. Table 1 shows the frequency of relatives by relation type for case subjects and a total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed.

Figure 1.

Patient selection overview.

Table 1.

Total number of probands and relatives included in the analysis

Relation type	No. of cases	No. of controls	Total No.
Proband	7266	36 318	43 584
First-degree relatives	32 604	170 125	202 729
Second-degree relatives	91 925	487 510	579 435
First cousins	100 033	516 933	616 966
Spouse	4689	22 984	27 673
Total	236 517	1 233 870	1 470 387

Individuals were followed from birth to time of cancer diagnosis, death, or the last date known of residence in Utah. Cancer diagnosis information on probands and family members was based on data from the Utah Cancer Registry (UCR), an original member of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program. UCR records have been linked to pedigree information in the UPDB. Site-specific counts and SEER site histology codes are included in Supplementary Table 1 (available online).

Familial standardized incidence ratio (FSIR) scores were calculated to identify families with a strong family history of discordant smoking-related cancers (10). Smoking-related cancers used to calculate FSIR included lung, oropharynx, nose and sinuses, larynx, pharynx, esophagus, stomach, pancreas, kidney, uterus, cervix, colon/rectum, ovary (mucinous), and acute myeloid leukemia. The FSIR was calculated by comparing the observed rate of smoking-related cancers in each family with the expected rate in the Utah population while controlling for birth year and gender. The FSIR weighed the contribution of each relative to the familial risk by the kinship coefficient, which was the probability that the relative shares an allele with the proband through a common ancestor. An FSIR for smoking-related cancer that exceeded 1 indicated that a proband’s relatives had higher than expected occurrence of smoking-related cancers. Families with a statistically significant smoking-related FSIR in the 75th percentile or greater (FSIR_Smoking > 1.048) were considered to be at high risk for smoking and were excluded from these analyses.

This study was approved by the Institutional Review Boards of the University of Utah (UU) and Intermountain Healthcare (IHC) by the Utah Resource for Genetic and Epidemiologic Research (www.researchutah.edu/rge/; IRB_00088870).

Statistical Analyses

Familial risk of multiple cancer subtypes was estimated using Cox regression to assess the risk of cancer in FDRs, SDRs, FCs, and spouses of urothelial cancer probands across cancer subtypes. Specific relatives (FDRs, SDRs, FCs, and spouses) of case subjects were compared with relatives of the matched control subjects. Separate hazard ratios were estimated for each relationship type. Covariates in the Cox regression models included sex and birth year. Time was measured in years, and individuals were right-censored at the time of death or at the last known date of residence in Utah (individuals must be Utah residents in order to see a diagnosis). All known relatives of UCa patients were included in the analyses, even if that relative had been previously counted. For example, for families containing multiple UCa diagnoses, each individual was considered a separate proband and risk among relatives of each proband was considered distinct, an approach that has been shown to lead to unbiased estimates of risk (4). Huber-White sandwich estimator of variance of regression parameters in the Cox models were used to correct for the nonindependence of observations within families (13). Family members of individuals without UCa were used as the reference group in all analyses. The first analysis was run to establish baseline risk among relatives and spouses for UCa as well as discordant cancers. Smoking-corrected analyses were performed that excluded families with high FSIR for smoking-related cancers to assess overall risk by relation type independent of smoking-related risk. Onset age analyses were estimated that stratified familial risk of UCa by age at diagnosis of the proband (age <50, 50–59, 60–69, and >70 years).

All statistical tests were two-sided, and a P value of less than .05 was considered statistically significant. Proportionality assumptions were tested using Schoenfeld residual tests as well as interacting the covariates with time.

Results

Forrest plots of the regression results are displayed in Figures 2 and 3 for all cancers with statistically significant risk identified in relatives of case subjects (a full list of results is shown in Supplementary Table 2, available online; Kaplan-Meier curves for the statistically significant results are displayed in Supplementary Figures 1 and 2, available online). The familial risk of any cancer was estimated first, and we found an increased risk in FDRs (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 1.03 to 1.09, P < .001) and SDRs (HR = 1.04, 95% CI = 1.02–1.07, P = .001) of UCa patients. To further investigate the association, we estimated familial risk of smoking-related cancers and found that family members of case subjects have higher risk: FDRs (HR = 1.13, 95% CI = 1.07 to 1.20, P < .001), SDRs (HR = 1.07, 95% CI = 1.02 to 1.12, P = .004), and spouses (HR = 1.21, 95% CI = 1.09 to 1.36, P = .001). Additional models were run to test the familial risk of UCa, and, as expected, relatives of UCa patients were at increased risk: FDRs (HR = 1.73, 95% CI = 1.50 to 1.99, P < .001) and SDRs (HR = 1.35, 95% CI = 1.21 to 1.51, P < .001). All aforementioned models were run excluding families with a high FSIR of smoking-related cancers (n = 1034), which slightly attenuated risk but did not eliminate it.

Figure 2.

Hazard ratios and 95% confidence intervals for Cox regression models for risk of urologic cancer in relatives of urothelial cancer patients by cancer site. Models were stratified by relation type and controlled for birth year and sex. Models excluding high familial standardized incidence risk families (n = 1034) are displayed on the right-hand side of the figure. Source: Utah Cancer Registry and Utah Population Database. FSIR = familial standardized incidence risk.

Figure 3.

Hazard ratios and 95% confidence intervals for Cox regression models for risk of other cancer types in relatives of urothelial cancer patients by cancer site. Models were stratified by relation type and controlled for birth year and sex. Models excluding high familial standardized incidence risk families (n = 1034) are displayed on the right-hand side of the figure. Source: Utah Cancer Registry and Utah Population Database. FSIR = familial standardized incidence risk.

When we further investigated this relationship by anatomic site, we found that in relation to population controls, FDRs of UCa patients had an increased risk of bladder (HR = 1.69, 95% CI = 1.47 to 1.95, P < .001), kidney (HR = 1.30, 95% CI = 1.08 to 1.57, P = .006), lung (HR = 1.34, 95% CI = 1.19 to 1.51, P < .001), and cervical cancer (HR = 1.25, 95% CI = 1.06 to 1.49, P = .01) (Figures 2 and 3). Again, we found that after excluding families with high FSIR for smoking-related cancers, the effect was slightly attenuated but not eliminated. SDRs were found to have statistically significantly increased risk of bladder (HR = 1.35, 95% CI = 1.20 to 1.50, P < .001), kidney (HR = 1.19, 95% CI = 1.02 to 1.38, P = .02), lung (HR = 1.23, 95% CI = 1.11 to 1.37, P < .001), and thyroid cancer (HR = 1.18, 95% CI = 1.03 to 1.35, P = .02) (Supplementary Table 2, available online). Unlike with FDRs, the elevated risk in lung and kidney cancer was not observed in SDRs of case subjects after exclusion of families with high FSIR of smoking-related cancers.

Spouses of case subjects had an increased risk of smoking-related cancers overall (HR = 1.21, 95% CI = 1.09 to 1.36, P < .001) (Supplementary Table 2, available online). When we investigated cancer risk by anatomic site, we found that spouses also had an increased risk of lung cancer (HR = 1.43, 95% CI = 1.11 to 1.85, P = .006), but this risk was not statistically significant after FSIR correction. For spouses, risks for cervical (HR = 1.57, 95% CI = 1.13 to 2.17, P = .007) and laryngeal cancer (HR = 2.68, 95% CI = 1.02 to 7.05, P = .04) were also elevated, but they remained statistically significant after the FSIR correction, and the correction actually increased the magnitude of the effect (although not outside of the original confidence intervals). FCs did not have increased cancer risk for specific cancer sites.

Table 2 shows risk of UCa in relatives of case subjects stratified by age of proband at diagnosis. The risk of UCa in relatives was strongest at earlier ages of diagnosis in the proband, as well as with closer genetic relationship. FDRs of UCa case subjects diagnosed between age 50 and 60 years had the highest risk (HR = 2.15, 95% CI =  1.60 to 2.88, P < .001), while risk in SDR and FC was highest when the UCa case subject was diagnosed younger than age 50 years: SDRs (HR = 1.75, 95% CI =  1.33 to 2.32, P < .001) and FCs (HR = 1.38, 95% CI = 1.01 to 1.90, P = .04). A general trend of decreasing risk with increasing genetic relatedness was observed across all age groups. Spouses did not have an elevated risk in any age subgroup.

Table 2.

Stratified risk of urothelial cancer in relatives by age of case subject^*

Relatives by age of case subject	No.	HR (95% CI)
<50 y	617
First-degree relatives		2.00 (1.28 to 3.13)
Second-degree relatives		1.75 (1.33 to 2.32)
First cousins		1.38 (1.01 to 1.90)
Spouse		N/A
50–60 y	1106
First-degree relatives		2.15 (1.60 to 2.88)
Second-degree relatives		1.21 (0.94 to 1.57)
First cousins		1.18 (0.97 to 1.43)
Spouse		0.84 (0.27 to 2.62)
60–70 y	1941
First-degree relatives		1.86 (1.53 to 2.27)
Second-degree relatives		1.30 (1.08 to 1.57)
First cousins		1.18 (1.04 to 1.34)
Spouse		1.12 (0.59 to 2.11)
70+ y	3602
First-degree relatives		1.53 (1.28 to 1.84)
Second-degree relatives		1.36 (1.17 to 1.57)
First cousins		0.97 (0.88 to 1.06)
Spouse		1.44 (0.99 to 2.06)

^*CI = confidence interval; HR = hazard ratio.

Sensitivity analyses were performed excluding relatives of case subjects with only upper tract urothelial carcinoma, and there was not a substantive difference in the results (results are not shown but are available from the authors upon request). Due to similar epidemiologic and genetic associations between upper and lower tract urothelial cancer, the two disease processes are presented together in the analysis. We tested the proportionality assumption in all models. With the exception of lung cancer in FDR and urothelial and bladder cancer in SDR, the proportionality assumption held. The risk of lung cancer decreases by 0.2% per 10-year increase in age in FDRs. The risk of both urothelial and bladder cancer decreases by 0.8% per 10-year increase in age in SDRs.

Discussion

Our findings suggest that familial clustering of cancers in relatives of case subjects with UCa have genetic or environmental roots independent of smoking-related behaviors. The pattern of risk among relatives was consistent with genetic causes, with FDRs having the highest risk for cancer. More distant relatives had elevated risks, but these were generally lower and more likely to be weak or statistically nonsignificant after our smoking correction. Surprisingly, relatives were not at increased risk for ureteral cancers. Though upper tract cancer is rare overall (around 5% of urothelial cancers [14]), more than 9% of our probands had upper tract urothelial cancer. This may suggest that the familial clustering of urothelial cancer is specific to lower tract cancers. Our findings also show that age of diagnosis of the proband is an important factor to consider, with family members of younger probands having increased risk for urothelial cancer.

Genetic risk factors could be the source of the increased risk of cancer in relatives of individuals diagnosed with UCa. Genetic risk of urothelial cancer has been established in Lynch syndrome (specifically in pathologic variants in the MSH2 gene) (15). Recent data have suggested that up to 22% of patients with bladder cancer have germline mutations in previously identified genes related to cancer (16). A recent genome-wide association study investigating single nucleotide polymorphisms (SNPs) in cancers has estimated the familial relative risk in bladder cancer to be 1.37 due to SNPs known to be heritable (18). They also found that very little of the risk could be attributed to loci currently recognized by the National Human Genome Research Institute to be associated with bladder cancer. The authors concluded that other, currently undiscovered, loci are likely the primary genetic determinants of familial risk.

Much like genetics, the impact of environmental exposures on familial cancer clustering is difficult to definitively quantify. Smoking behavior tends to cluster in families, making it difficult to differentiate between smoking-related exposures, environmental exposures, and shared genes (19). This is even more complicated by the undetermined risk of secondhand smoke on the risk of bladder cancer (20,21). In our study, similar to previous bladder cancer studies, relatives had a higher risk of thyroid, lung, and kidney cancer, as well as an increased overall cancer risk (1,2,4,22). Our study found that after exclusion of families with a high FSIR for smoking-related cancers, the magnitude and statistical significance of risk for discordant cancers was oftentimes attenuated in SDRs and spouses, but not FDRs. Though specific genetic sequencing is unavailable for this cohort, the persistence of risk in FDRs despite correction for smoking risk could suggest an underlying genetic or other environmental linkage between the cancers being diagnosed in these relatives.

Interestingly, in spouses, the FSIR correction increased the risk for cervical and laryngeal cancer. These cancer subtypes, including bladder cancer, have also been found to be associated with high-risk human papillomavirus (HPV) infection (23–25). Though the literature on spousal cancer risk attributable to HPV is limited, this association has been identified and could explain many of the cancer risk patterns identified for spouses in our cohort (25). However, HPV infection does not explain the lung cancer risks initially identified in spouses, which became statistically nonsignificant after the FSIR correction for smoking status, which suggests that multiple environmental mechanisms may be leading to spousal clustering of risk.

Independent of other factors, there is strong evidence that a younger age at diagnosis further increases the risk of cancers in relatives (2,4,26). In addition to excluding suspected smoking behaviors, our study also performed a subanalysis utilizing patient age as a factor in UCa risk in relatives. Our findings mirror those found in previous bladder cancer studies, with urothelial cancer diagnosis in younger patients being associated with an increased risk of urothelial cancer (1). Although there was statistically significant overlap between the different age groups’ confidence intervals, the highest risk in relatives was consistently among the younger age group stratifications. The mechanism underlying this pattern could be that the greater the shared genetic or environmental insult, the earlier and more likely a potential cancer will develop.

The differences between our methods and previously published data yield important information. Our FSIR correction for smoking-related cancers allowed us the first look at cancer clustering in relatives of UCa patients potentially independent of smoking risk. Our findings, in conjunction with previous studies, provide evidence for familial clustering in urothelial cancer and that, in general, risk of cancer attenuates with increased genetic distance to the proband and increasing age of the proband at diagnosis. Our findings also highlight the importance of looking across a spectrum of tumors for shared familial risk. Removing the site-specific constraints normally placed on familial cancer clustering studies may reveal novel patterns of risk in families and allow us to identify the genetic and environmental determinates of specific cancer subtypes.

A few limitations to this study are worth noting. The UPDB cohort has a higher percentage of white individuals than the general population. It also has a high proportion of members of the Church of Jesus Christ of Later Day Saints (LDS) higher fertility rates, and lower rates of smoking and alcohol consumption (9,27). As discussed, some of the familial clustering of risk may be due to health behaviors, such as smoking, and therefore our estimates may be lower than in the general US population. However, lower rates of smoking and alcohol consumption make it easier to identify familial patterns that may be genetic in nature. Also, although the exclusion of families with an elevated FSIR attenuated many of the smoking-related cancers in our analysis, it was likely an imperfect indicator of smoking status at the level of the individual. With that in mind, future studies should continue to strive for more definitive indicators of smoking status. Lastly, although we found statistically significant excess risk in closer family members, we lacked access to specific genetic information. Future studies should work to identify whether genetic mechanisms underlie these cancer patterns as well as determining if these risks are specific to lower tract cancer exclusively. The families in this cohort with familial clustering of non-smoking-related UCa could be used for genetic predisposition identification via genetic linkage studies.

Funding

This work was supported by the Genitourinary Malignancies Disease-Oriented Team, HCI Cancer Center Support Grant (grant number P30CA042014), and National Institutes of Health funding (grant number 1K12HD085852-01).

Note

The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.