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Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case-Control Study
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 present a population−based study of cancer risks in relatives of bladder cancer patients with exclusion of variant subtypes, improving the understanding of familial cancer clustering in urothelial cancer.
Methods: Probands with urothelial carcinoma from the Utah Cancer Registry were matched 1:5 to controls from the Utah Population Database. First-degree relatives, second-degree relatives, first cousins, and spouses were evaluated for cancer risks. To correct for smoking status we performed a secondary analysis excluding families with elevated rates of smoking-related cancers.
Results: The relatives of 7,266 probands and 36,318 matched controls were analyzed. First and second-degree relatives had an increased risk for any cancer diagnosis (HR:1.06, p=0.0008; HR:1.04, p=0.002) and urothelial cancer before and after suspected smoking correction (HR:1.72, p<0.0001; HR:1.67, p<0.0001). Site-specific analysis after smoking correction found increased risks for bladder (HR:1.68, p<0.0001), kidney (HR:1.29, p=0.007), cervical (HR:1.24, p=0.01), and lung cancer (HR:1.34, p<0.0001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR:1.35, p<0.0001) and thyroid cancer (HR:1.17, p=0.03). Spouses showed an increased risk in laryngeal (HR:2.84, p=0.04) and cervical cancer (HR:1.57, p=0.01).
Conclusion: Our results suggest familial urothelial cancer clustering independent of smoking, with increased cancer risks in closer relatives, suggesting shared genetic or environmental roots. Families with significant risks for non-smoking related urothelial cancer would provide high yield grounds for genetic linkage studies.
Studies that examined familial aggregation of bladder cancer have suggested there is a strong familial component to bladder cancer.[1-4] For example, brothers of a proband diagnosed before the age of 45 have approximately 7 times the risk of disease development. 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 (non-bladder) cancers in relatives.[1-4] However, due to limitations with cohort selection and the failure to adjust for smoking status the relevance of this information 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 non-urothelial cancers are distinct. Squamous cell carcinoma for example is more likely in females and is most strongly associated with chronic infection or irritation. In fact, lower tract urothelial carcinoma could be closer in relation to upper tract urothelial carcinoma than the other subtypes of bladder cancer; epidemiologically speaking, histology is potentially more important than site.
Another important issue affecting 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, kidney, 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 patient’s risk.[8, 9] 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%. Probands with non-urothelial subtypes of cancer were excluded from this analysis to better characterize the pattern within this subtype. Primary analysis was 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. Secondary analysis was performed excluding families with cancer-clustering patterns that are congruent with smoking-related behaviors (determined by Familial Standardized Incidence Risk or FSIR). A tertiary analysis was performed that stratified familial risk of UCa 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 the risk of UCa in family members would be higher for probands diagnosed at younger ages.
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 its sample size, pedigree complexity, and linkages across data sources.[12, 13] 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 patients (Probands=7,266). Among probands, average age at diagnosis was 72. 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 controls 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 probands and controls were selected from the UPDB. First-degree relatives (FDRs) included parents, children, and siblings (Probands=32,604, Controls=170,125). Second-degree relatives (SDRs) included grandparents, grandchildren, aunts/uncles, and nieces/nephews (Probands=91,925, Controls=487,510). Risks in first cousins (FCs) (Probands=100,033, Controls=516,933) and spouses (Probands=4,689, Controls=22,984) of UCa patients were also evaluated. Table 1 shows the frequency of relatives by relation type for probands and controls.
The UPDB permits following individuals from birth to time of cancer diagnosis, death, or the last date known to be residing in Utah. Cancer diagnosis information on probands and family members were 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.
Familial standardized incidence ratio (FSIR) scores were calculated to identify families with a strong family history of discordant smoking related cancers. Smoking related cancers considered in our FSIR analysis 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 to 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 one indicated that a proband’s ancestor had higher than expected occurrence of smoking-related cancers. Families with a significant smoking-related FSIR in the 75th percentile or greater (FSIRSmoking > 1.048) were considered to be at high risk for smoking and excluded from these analyses.
This study was approved by the Institutional Review Boards of the UU and IHC by the Utah Resource for Genetic and Epidemiologic Research (www.researchutah.edu/rge/) #IRB_00088870.
Familial risk of multiple cancer subtypes were 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 probands were compared to relatives of the matched controls. Separate analyses were run 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 last known date of residence in Utah (individuals must be Utah residents in order to see a diagnosis). All 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. Huber-White sandwich estimator of variance of regression parameters in the Cox models were used to correct for the non-independence of observations within families. Family members of individuals without UCa were used as the reference group in all analyses. The primary analysis was run to establish baseline risk among relatives and spouses for UCa as well as discordant cancers. Secondary analysis was performed that excluded families with high FSIR for smoking related cancers to assess overall risk by relation type independent of smoking related risk. A tertiary analysis was performed that stratified familial risk of UCa by age at diagnosis of the proband (< age 50, age 50 – 59, age 60 – 69, and over age 70).
Forrest plots of the regression results are displayed in Figures 2 and 3 for all cancers with significant risk identified in relatives (a full list of results is shown in Supplementary Table 2). When using broad categories, we found an increased risk for diagnosis of any cancer in FDRs (HR=1.06; 95% CI=1.02-1.09), and SDRs (HR = 1.04; 95% CI = 1.01–1.07), as well as smoking related cancer in FDRs (HR=1.13; 95% CI=1.07-1.20), SDRs (HR=1.07; 95% CI=1.02-1.12), and spouses (HR=1.21; 95% CI=1.08-1.35). Increased risk specific for UCa was also found in FDRs (HR = 1.72; 95% CI = 1.49–1.98) and SDRs (HR = 1.35; 95% CI = 1.21–1.50). Excluding families with a high FSIR of smoking related cancers (n=1034) slightly attenuated risk, but did not eliminate it.
When we further investigated this relationship by anatomic site, we found FDRs had an increased risk of bladder (HR = 1.68; 95% CI = 1.46–1.94), kidney (HR = 1.29; 95% CI = 1.07–1.56), lung (HR = 1.34; 95% CI = 1.19–1.51), and cervical cancer (HR = 1.24; 95% CI = 1.05–1.47). 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 significantly increased risk of bladder (HR = 1.35; 95% CI = 1.20–1.50), kidney (HR = 1.18; 95% CI = 1.02–1.37), lung (HR = 1.23; 95% CI = 1.11–1.37), and thyroid cancer (HR = 1.17; 95% CI = 1.01–1.34). Unlike with FDRs, the elevated risk in lung and kidney cancer was not seen in SDRs after exclusion of families with high FSIR of smoking-related cancers.
Spouses had an increased risk of smoking-related cancers overall (HR = 1.21; 95% CI = 1.08–1.35). When we investigated this relationship by subtype, we found that spouses also had an increased risk of lung cancer (HR = 1.40; 95% CI = 1.08–1.80) but this risk was not significant after FSIR correction. For spouses, only cervical (HR = 1.64; 95% CI = 1.18–2.28) and laryngeal cancer (HR = 2.84; 95% CI = 1.05–7.66) risks were significantly elevated after the FSIR correction, and the correction actually increased these risks. FCs did not have increased cancer risks on subtype analysis.
Table 2 shows risk of UCa in relatives 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 probands diagnosed between ages 50 and 60 had the highest risk (HR=2.15; 95% CI= 1.60- 2.88), compared to diagnosis age <50 for SDRs (HR=1.75; 95% CI= 1.33- 2.32), and FCs (HR=1.38; CI=1.01- 1.90). 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.
Sensitivity analyses were performed excluding individuals with only upper tract urothelial carcinoma, and there was not a substantive difference in the results. Due to similar epidemiologic and genetic associations between upper and lower tract urothelial cancer, the two disease processes are presented together in the analysis.
Our findings suggest that familial clustering of cancers in probands 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 insignificant 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) 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 risks 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). Recent data has suggested that as much as 22% of patients with bladder cancer have germline mutations in previously identified genes related to cancer. Additionally, analysis of UCa within the Cancer Genome Atlas project has shown consistent somatic mutations in 32 genes affecting cell cycle regulation, chromatin regulation, and kinase signaling. Of those genes, 9 of the 32 had not been previously reported being involved in any type of cancer. A recent Genome-wide association study (GWAS) investigating single-nucleotide polymorphisms (SNPs) in cancers has estimated the familial relative risk in bladder cancer to be 1.37 due to SNPs related heritability. 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. 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. This is even more complicated by the undetermined risk of secondhand smoke on the risk of bladder cancer.[21, 22] 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, 23] Our study found that after exclusion of families with a high FSIR for smoking related cancers, the magnitude and significance of risk for discordant cancers was often times attenuated in SDRs and spouses, but not FDRs.
Interestingly, the FSIR correction increased the spouses risk for cervical and laryngeal cancer. While the risk patterns in spouses could potentially show that the FSIR correction does not fully characterize smoking status at the level of the individual, these cancer subtypes, including bladder cancer, have also been found in association with high risk human papillomavirus (HPV) infection.[24-26] Though the literature on spousal cancer risk attributable to HPV is limited, this association has been identified and could explain much of the cancer risk patterns identified for spouses in our cohort. While HPV infection does not explain the lung cancer risks initially identified in spouses, our FSIR correction attenuated lung cancer risk as well as other smoking-related subtypes in spouses and other family members and performed as a reasonable surrogate of smoking status. 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.
Independent of other factors there is strong evidence that a younger age at diagnosis further increases the risk of cancers in relatives.[2, 4, 27] In addition to suspected smoking behaviors, our study also performed a sub-analysis 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. Although there was significant overlap between the different age group’s 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. 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. However, Utah has half the rate of smoking compared to the United States overall so our study is much less likely to be confounded by smoking compared to previous studies. With that in mind, future studies should continue to strive for more definitive indicators of smoking status. Although we found 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.
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Table 1. Total Number of Relatives Included in the Analysis
|First Degree Relatives||32604||170125||202729|
|Second Degree Relatives||91925||487510||579435|
Table 2. Stratified Risk of Urothelial Cancer in Relatives by Age of Proband
|Proband Age < 50
|Relationship||Hazard Ratio||95% CI|
|Proband Age 50 – 60
|Relationship||Hazard Ratio||95% CI|
|Proband Age 60 – 70
|Relationship||Hazard Ratio||95% CI|
|Proband Age 70+
|Relationship||Hazard Ratio||95% CI|
Figure 1. Patient Selection Overview
Figure 2, Panel A. Cancer Risk in Relatives by Type
Figure 1. 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 FSIR families (n=1034) are displayed on the right hand side of the figure. Source: Utah Cancer Registry and Utah Population Database.
Figure 2. Cancer Risk in Relatives by Type
Figure 2. 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 FSIR families (n=1034) are displayed on the right hand side of the figure. Source: Utah Cancer Registry and Utah Population Database.
Table 1. Proband Site Case Count/Histology
|Site||SEER Site No||Included Histologies||Number of Cases|
|Bladder||29010||8010, 8120, 8122, 8130, 8131||6603|
|Renal Pelvis||29020||8010, 8120, 8130||495|
|Ureter||29030||8010, 8120, 8130||168|
Table 2. Hazard Ratio for Relatives by Type
|Cancer Type||Relative Type||Bladder and Upper Tract|
|Smoking Related Cancer||FDR||1.13||1.07-1.20|
|Urothelial (excluding high FSIR smoking families)||FDR||1.67||1.45-1.93|
|Bladder (excluding high FSIR smoking families)||FDR||1.65||1.43-1.91|
|Kidney (excluding high FSIR smoking families)||FDR||1.27||1.04-1.54|
|Lung (excluding families with high FSIR for smoking related cancer)||FDR||1.39||1.19-1.64|
|Cervix (excluding high FSIR smoking families)||FDR||1.24||1.03-1.48|
|Thyroid (excluding high FSIR smoking families)||FDR||0.95||0.74-1.21|
|Larynx (excluding high FSIR smoking families)||FDR||1.29||0.88-1.91|
|Ureter (excluding high FSIR smoking families)||FDR||0.97||0.20-2.21|
|Myeloma (excluding high FSIR smoking families)||FDR||1.07||0.83-1.40|
|Brain and CNS||FDR||0.99||0.81-1.22|
|Female Organs: Corpus Uteri, Uterus NOS, Ovary, Vagina, Other Female Genital Organs||FDR||1.02||0.91-1.15|
|Male Organs: Testis, Penis, Other Male Genital Organs||FDR||1.18||0.82-1.69|
|Colon: Cecum, Appendix, Ascending Colon, Hepatic Flexure, Transverse Colon, Splenic Flexure, Descending Colon, Sigmoid Colon, Large Intestine||FDR||1.07||0.95-1.20|
|Oral: Other Oral Cavity and Pharynx, Tongue, Salivary Gland, Floor of Mouth, Gum and Other Mouth, Tonsil||FDR||0.99||0.75-1.30|
|Pharynx: Nasopharynx, Oropharynx, Hypopharynx, Other Oral Cavity and Pharynx||FDR||1.36||0.79-2.36|
|Paranasal: Nose, Nasal Cavity, and Middle Ear||FDR||1.21||0.56-2.60|