Utah Population Database Research Articles

Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk.

Aim:Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity.Methods:We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity.Results:We identified a genome-wide significant region (P = 1.9 × 10−7, LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression.Conclusion:SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).

Are paternal or grandmaternal age associated with higher probability of trisomy 21 in offspring? A population-based, matched case-control study, 1995-2015.

Fetal aneuploidy risk increases with maternal age, but the majority of pregnancies complicated by trisomy 21 occur in younger women. It has been suggested that grandmaternal and/or paternal age may also play a role. To assess the association between grandmaternal and paternal age and trisomy 21. For the grandmaternal assessments, we included all offspring with trisomy 21 in a statewide birth defects surveillance system (1995-2015) that could be linked to 3-generation matrilineal pedigrees in the Utah Population Database. Ten sex/birth year-matched controls were selected for each case (770 cases and 7700 controls). For the paternal assessments, our cohort included all trisomy 21 cases (1995-2015) where both the mother and father resided in Utah at the time of birth (1409 cases and 14090 controls). Ages were categorised by 5-year intervals (reference: 25-29years). Conditional logistic regression, adjusting for potential confounding factors, was used to model the association between grandmaternal and paternal age and trisomy 21. No association between grandmaternal age and trisomy 21 was detected, whether age was assessed continuously (adjusted odds ratio [OR] 1.01, 95% confidence interval [CI] 0.98, 1.03) or categorically after adjusting for grandmaternal and grandpaternal race/ethnicity and grandpaternal age. Compared to fathers aged 20-29years, fathers <20years (OR 3.15, 95% CI 1.99, 4.98) and 20-24years (OR 1.39, 95% CI 1.11, 1.73) had increased odds of trisomy 21 offspring, after adjusting for maternal and paternal race/ethnicity and maternal age. Results were consistent after excluding stillbirths, multiples, and trisomy 21 due to translocation or mosaicism. Maternal age is an important risk factor for trisomy 21 offspring; however, this population-based study shows that that young paternal age is also associated with trisomy 21, after taking into account maternal age and race/ethnicity.

15947 Inaccuracy of self-reported family history of melanoma in high-risk patients

Family history of melanoma is a known major risk factor for melanoma. However, self-reported family histories for numerous cancers, including melanoma, are commonly inaccurate. Three large melanoma studies have explored this with positive predictive values (PPVs), 28%-83%. Given these wide variations, we explored this question in individuals at high-risk of melanoma, and thus, more likely to be aware of their family history of melanoma. We queried the Utah Population Database (UPDB), a unique, extensive family history database linking >11,000,000 individuals with public records (driver’s license, marriage/divorce records), medical records and death records. This offers a more complete multi-generational dataset for a much larger cohort than would be feasible through manual chart review and is the largest cohort study to date. Charts from 1780 high-risk patients (having at least one melanoma risk factor) were reviewed to quantify self-reported family history of melanoma. These data were combined with UPDB and Utah Cancer Registry data serving as the “gold standard.” Self-reported family history of melanoma in first- and second-degree relatives had an overall sensitivity of 62%, specificity of 67%, PPV of 31%, and NPV of 89%, with increased accuracy for first-degree relatives. A personal history of melanoma was the only factor associated with increased accuracy in self-reported family history of melanoma. Age, sex, number of nevi, and number of prior personal melanomas were not significant. Dermatologists should educate patients on the differences between melanoma, nonmelanoma skin cancer and pre-cancers. Confirming self-reported family history of melanoma will limit over-screening of otherwise low-risk patients.

The Risk of Cardiovascular Disease Among Ovarian Cancer Survivors

Background: Very few studies have investigated cardiovascular disease (CVD) risk among ovarian cancer survivors in a population-based study. We aimed to estimate CVD risk among ovarian cancer survivors compared to women from the general population in a population-based study. Methods: A cohort of 1,271 patients with ovarian cancer diagnosed from 1996 to 2012 in the Utah Cancer Registry and 5,289 age-matched women from the general population in the Utah Population Database was identified. CVD outcomes were available in electronic medical records and statewide healthcare facilities data. Cox Proportional Hazards models were used to estimate hazard ratios (HRs) for CVD at 1-5 years and >5 years after the index date. Findings: Increased risks were observed 1-5 years after cancer diagnosis for ovarian cancer survivors in comparison with the general population for hypertension (HR=1·14, 95% CI, 1·01-1·29), cerebrovascular disease (HR=1·42, 95% CI, 1·06-1·89), and diseases of the heart (HR=1·81, 95% CI, 1·60-2·04), the arteries (HR=1·97, 95% CI, 1·67-2·33), and the veins and lymphatics (HR=2·75, 95% CI, 2·36-3·22). Elevated risks were still observed for diseases of the arteries (HR=1·31, 95% CI, 1·06-1·61) and the veins and lymphatics (HR=1·80, 95% CI, 1·48-2·18) >5 years after cancer diagnosis. Interpretation: Ovarian cancer survivors had higher risks of several CVD outcomes compared with women from the general population. The results support the consideration of monitoring and/or initiation of primary prevention for CVD outcomes among ovarian cancer survivors. Funding: This work was supported by a grant from the NCI (R21 CA185811), the Marian Bishop Award from the Department of Family and Preventive Medicine at the University of Utah and the NCRR grant, “Sharing Statewide Health Data for Genetic Research” (R01 RR021746, G. Mineau, PI) with additional support from the Utah State Department of Health and the University of Utah. Declaration of Interests: None reported. Ethics Approval Statement: We obtained approval from the University of Utah’s Resource for Genetic and Epidemiologic Research (UPDB oversight committee) and the University of Utah Institutional Review Board.

Cluster Detection of Cancer Incidence: Analyzing Childhood Residential Location Linked to Later Life Cancer Records

BackgroundChildhood environmental exposures are now recognized contributors to cancer later in life. However, direct measurement of environmental contaminants is not feasible using most retrospective datasets and potentially long latency periods exist between exposures and cancer incidence. Investigating the spatiotemporal patterns of cancer clustering is one useful approach to evaluate the importance of childhood environment on adult cancer risk. We assessed spatial clustering of cancer incidence in 1966-2017 based on early life location defined by household Enumeration District (ED) at the 1940 US Census.MethodsA cohort of all individuals born 1930-1939 was selected from the Utah Population Database. Incident cancer cases for 25 cancer types were identified beginning in 1966 from the Utah Cancer Registry or by death records and linked to geocoded population-weighted ED centroids. Follow-up time was measured as years from 1940 to first primary cancer diagnosis, death, or last known residence in Utah. Spatial scan statistic with a purely elliptic scanning window was used to identify spatial clustering of EDs with high rates of cancer assuming the discrete Poisson model. Separate analyses were completed for each cancer type. Our analysis included 92,279 individuals who contributed 4,674,932 person-years representing 826 EDs.ResultsAverage follow-up time was 50.9 years (range 0.58-78 years). Cancer was diagnosed in 21% of individuals on follow-up. The number of individuals in an ED ranged from 11-518 (mean = 111). We detected four clusters of excess risk of breast (Relative Risk [RR]=1.27, p=0.028), leukemia (RR=1.92, p=0.033), lung (RR=1.89, p=0.013), and prostate cancers (RR=1.27, p=0.0089).ConclusionsWhile this study was hypothesis generating and did not test for environmental contaminants directly, we demonstrate that early life location may contribute to later health outcomes. With the growing availability of longitudinal databases that compile records across the lifespan, spatial cluster detection methods offer unique opportunities to improve understanding of chronic disease etiology.

Association between Obstructive Sleep Apnea and Exfoliation Syndrome: The Utah Project on Exfoliation Syndrome

Exfoliation syndrome (XFS), the most common recognizable cause of open-angle glaucoma worldwide, is a systemic disorder with genetic predisposition due to variations in lysyl oxidase-like 1 (LOXL1) function, leading to altered elastin matrices in ocular and systemic tissues. Obstructive sleep apnea (OSA) is a highly prevalent disorder also involving elastic tissue dysfunction and is associated with glaucoma. Because of the similarities between the disorders, we sought to uncover any relationship in the prevalence of these diagnoses. Case-control, retrospective cohort study. A cohort of 81 735 patients diagnosed with OSA at ages 50 to 90 years was identified from medical records from 1996 to 2017 in the Utah Population Database. Case subjects were matched to random controls on sex and birth year in a 4:1 ratio. International Classification of Diseases, Ninth Revision (ICD-9) codes or their Tenth Revision equivalent were used to define a diagnosis of OSA (ICD-9 327.23) and a diagnosis of XFS (ICD-9 365.52 and 366.11). Conditional logistic regression odds ratios (ORs) accounting for individual matching on sex and birth year were used to estimate the risk of XFS in patients with OSA. Models included adjustment for race, obesity, tobacco use, hypertension (HTN), atrial fibrillation (AF), and chronic obstructive pulmonary disease (COPD). Whether patients with OSA have an increased risk of diagnosis of XFS compared with controls without OSA. There was an increased risk of an XFS diagnosis in patients with OSA compared with non-OSA controls (OR, 1.27; 95% confidence interval [CI], 1.02-1.59; P= 0.03). In a stratification of patients by HTN diagnosis history, patients with OSA and HTN exhibited an increased risk of XFS compared with non-OSA controls with HTN (OR, 2.67; 95% CI, 2.06-3.46; P < 0.0001). Patients with OSA may be at an increased risk of XFS compared with patients without OSA, particularly in patients with a history of HTN.

Hospitalization following eating disorder diagnosis: The buffering effect of marriage and childbearing events.

Eating Disorders (ED) are defined as abnormal eating behaviors, stemming from an obsession with food, body weight, or body shape. EDs affect 10 million men and 20 million women in the US, with an estimated 15% lifetime prevalence among women. An ED diagnosis is often accompanied with a host of adverse physical and mental health outcomes, including a heightened risk for suicidality. Given the complex comorbidities associated with EDs, treatment occurs in inpatient and outpatient settings. This study used linked administrative and health records from the Utah Population Database to create a cohort of women n = 4183 and men n = 423 who had a known diagnosis of ED between 1995 and 2015. Cox proportional hazard regression was used to model ED-related hospitalization trajectories, including subsequent risk for suicidality/self-injurious behavior-related hospitalization. To better estimate the risk profiles associated with different health care utilization patterns, models explored how family-related life course events (childbirth, marriage transitions) and sociodemographic characteristics (race, sex, and median income at census-block) modify hospitalization trajectories following initial diagnosis. Results suggested that increased outpatient treatment was associated with reduced risk of initial ED-related hospitalization, but higher risk for subsequent ED-related hospital readmission. In addition, transition to marriage (i.e., getting married) was associated with reduced risk of ED-related and suicidality/self-injurious behavior-related hospitalizations (initial hospitalization and subsequent readmission). Increased number of children was only associated with reduced risk of initial ED-hospitalization, but not readmission. When assessing individuals' risk for ED-related hospitalizations, social and health services researchers should contextualize treatment trajectories within the individual's life experiences, particularly marital transitions, while simultaneously considering sociodemographic characteristics and utilization of outpatient care. Future research should further examine whether marriage represents an important turning point in the health trajectories of individuals with EDs.

The Effects of Marital Status, Fertility, and Bereavement on Adult Mortality in Polygamous and Monogamous Households: Evidence From the Utah Population Database

Although the associations among marital status, fertility, bereavement, and adult mortality have been widely studied, much less is known about these associations in polygamous households, which remain prevalent across much of the world. We use data from the Utah Population Database on 110,890 women and 106,979 men born up to 1900, with mortality follow-up into the twentieth century. We examine how the number of wife deaths affects male mortality in polygamous marriages, how sister wife deaths affect female mortality in polygamous marriages relative to the death of a husband, and how marriage order affects the mortality of women in polygamous marriages. We also examine how the number of children ever born and child deaths affect the mortality of men and women as well as variation across monogamous and polygamous unions. Our analyses of women show that the death of a husband and the death of a sister wife have similar effects on mortality. Marriage order does not play a role in the mortality of women in polygamous marriages. For men, the death of one wife in a polygamous marriage increases mortality to a lesser extent than it does for men in monogamous marriages. For polygamous men, losing additional wives has a dose-response effect. Both child deaths and lower fertility are associated with higher mortality. We consistently find that the presence of other kin in the household—whether a second wife, a sister wife, or children—mitigates the negative effects of bereavement.

INCREASED RISK FOR CONGENITAL MALFORMATIONS IN RELATIVES OF MEN WITH POOR SEMEN QUALITY: EVIDENCE FROM THE UTAH POPULATION DATABASE (UPDB)

Male reproductive health is a marker of individual somatic health and more recently has been associated with familial health. Familial studies offer a unique opportunity to quantity the effect of genetic and shared environmental exposures on male subfertility and birth outcomes. We have previously shown an increased risk of death from congenital malformations (CM) in relatives of men with lower semen parameters. We examine the association between markers of poor semen quality in men presenting for infertility workup and any CM in their relatives, within the Utah Population Database (UPDB).

Familial Risk of Abdominal Aortic Aneurysm and Implications for Population Screening

The likelihood of developing an abdominal aortic aneurysm (AAA) is known to be attribuTable to inheriTable risk factors, although the degree of familial risk has not been clearly defined. We sought to quantify the familial risk of AAAs according to the degree of relationship to a patient, specifically first-degree relatives (FDRs), second-degree relatives (SDRs), and first cousins (FCs) of patients with a diagnosis of an AAA. We performed a retrospective case-control study using the Utah Population Database to identify all patients with a diagnosis of an AAA in the state of Utah from 1969 to 2019. Age- and sex-matched controls were identified for all AAA cases and their relatives in a 10:1 ratio. Patient age at the AAA diagnosis was stratified into 4 categories (0-44, 45-54, 55-64, and >65 years). Nonproportional hazard modeling was used to estimate the familial risk for relatives of patients with AAAs and the effect of gender and age on an AAA diagnosis. A total of 6968 patients with AAA (cases) were identified, of whom 71.8% were male. There were 36,825 FDRs, 107,291 SDRs, and 99,818 FCs, with 2.8 million matched controls. The risk of an AAA diagnosis was directly related to how closely an individual was related to a patient, with a hazard ratio (HR) of 3.02 for FDRs (95% confidence interval [CI], 2.75-3.31; P < .001), 1.6 for SDRs (95% CI, 1.42-1.72; P < .001), and 1.3 for FCs (95% CI, 1.26-1.42; P < .001; Fig). Furthermore, the risk of a diagnosis of AAA varied by age within the different relative groups. Among the individuals with a FDR, the risk of an AAA diagnosis was significantly greater compared to that for the age-matched controls in both the 0- to 44-year (HR, 8.29; P = .03) and 55- to 64-year (HR, 4.65; P < .001) age groups. Finally, a slightly lower risk of an AAA diagnosis was found for the FDRs of male versus female cases (HR, 0.91; P = .018) that was not seen in the other relative categories. We found an incremental increase in the risk of an AAA according to the degree of familial relationship. Also, for FDRs, the risk varied by the sex of the index case. Moreover, our data have suggested that risk of an AAA diagnosis for FDRs is present at much younger ages than what traditional screening captures. These findings have implications for population AAA screening programs, which, at present, do not consider familial risk.

Abstract 3485: Body mass index and mammographic density among Native Hawaiians and Pacific Islanders

Abstract Background: Mammographic density is an important breast cancer risk factor, yet data on mammographic density is limited for some racial/ethnic groups, including Native Hawaiians and Pacific Islanders (NHPI). Obesity is highly prevalent in the NHPI population and prior work, primarily in non-Hispanic White (NHW) women, has reported that high body mass index (BMI) is inversely associated with mammographic density but positively associated with risk of breast cancer. We used data from the Utah Population Database (UPDB) to estimate the association between BMI and mammographic density in Utah's NHPI population and evaluate if the association differs for NHPI women compared to NHW women. Methods: We included women ages 18-79 years with at least one mammogram from 2005-2012 and no history of breast cancer. Data on BMI and race/ethnicity were collected from the UPDB, and mammographic density was evaluated using Breast Imaging Reporting and Data System (BIRADS) scores. We estimated the association between BMI and BIRADS using multinomial logistic regression adjusted for age and stratified at age 55 (a proxy for menopausal status). Heterogeneity by race/ethnicity was evaluated using likelihood ratio tests. Results: Our analyses included data from 102 Native Hawaiian, 112 Samoan, 344 other Pacific Islander, and 143,259 NHW women. High mammographic density (BIRADS=4) was less common among Samoan women (2.7%) and other Pacific Islanders (4.7%) compared to NHW women (5.8%), but more common among Native Hawaiians (11.8%). Age-standardized BMI was highest in Samoan women (mean=32.3, SD=6.3) followed by other Pacific Islander women (mean=31.2, SD=7.1) then Native Hawaiian women (mean=27.8, SD=6.4), and lowest among NHW women (mean=26.1, SD=5.4). Among women younger than age 55, a one-unit increase in BMI was associated with 0.76 (95% CI=0.69-0.84) times lower odds of high (BIRADS=4) versus low (BIRADS=1) breast density in NHPI women. The comparable odds ratio (OR) in NHW women was 0.66 (95% CI=0.65-0.66; p-heterogeneity=6.9 × 10^-10). For women age 55 and older, the association between BMI and mammographic density was stronger among NHPI women, OR=0.62 (95%CI=0.45-0.84), compared to NHW women, OR=0.70 (95%CI=0.69-0.72; p-heterogeneity=0.018). Discussion: Mammographic density differs among racial/ethnic subgroups of the NHPI population with Native Hawaiians having the highest mammographic density. Given the high prevalence of obesity in the NHPI population and evidence that the association between BMI and mammographic density may differ by race/ethnicity, more research is needed to understand how BMI and mammographic density influence risk of breast cancer in understudied racial/ethnic minorities, such as NHPIs. Citation Format: Mollie E. Barnard, Tarun Martheswaran, Jennifer A. Doherty, Karen Curtin. Body mass index and mammographic density among Native Hawaiians and Pacific Islanders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3485.

Abstract 5795: Long-term diabetes risk among ovarian cancer survivors in a population-based cohort study

Abstract Objective. In the United States, ovarian cancer is the eleventh most common female cancer and the fifth most common cause of cancer death among women. Although incidence and death rates have been declining over the last 10 years, the 5-year survival rate is 47.6%. Diabetes was the seventh leading cause of death in the United States and is associated with an increased mortality rate among cancer patients. While previous studies have examined the association between diabetes and the risk of ovarian cancer, there are very few studies investigating the risk of diabetes after an ovarian cancer diagnosis. We previously reported increased risks of type I and II diabetes among endometrial cancer survivors, but there is no previous study, to our knowledge, that examined the risk of diabetes among ovarian cancer survivors. The aim of this study was to investigate long-term diabetes risk among ovarian cancer survivors compared with a general population of women. Methods. Ovarian cancer patients diagnosed from 1996 to 2012 in the Utah Cancer Registry were matched to up to 5 cancer-free women on birth state and birth year using the Utah Population Database. Diabetes diagnoses were identified with ICD-9 codes from statewide ambulatory surgery records, statewide inpatient databases and electronic medical records. We estimated hazard ratios with Cox Proportional Hazards models to: (1) investigate risk for diabetes after cancer diagnosis among ovarian cancer survivors compared with the general population, and (2) examine risk factors for type II diabetes among ovarian cancer survivors. Results. A total 1,520 ovarian cancer patients and 5,709 women from the general population were included in the final cohort. A slightly higher proportion of ovarian cancer patients were obese at baseline (16.3%) than the general population cohort (14.9%). Ovarian cancer survivors had a higher risk of type II diabetes in the first year after cancer diagnosis (HR=3.09, 95%CI=2.09, 4.56) and overall (HR=1.52, 95%CI=1.23, 1.88) compared with the general population. However, associations between ovarian cancer and type II diabetes were not observed in the later follow up periods. High BMI was a significant risk factor for type II diabetes among ovarian cancer survivors, with a dose-response relation (overweight; HR=1.81, 95%CI=1.21, 2.71, obese; HR=2.48, 95%CI=1.61, 3.83, P-trend &amp;lt;0.001). Clinical factors such as cancer treatment, stage, and histology did not contribute to an increased risk of type II diabetes among ovarian cancer patients. Other factors such as race and baseline comorbidities were also not associated with type II diabetes risk among ovarian cancer patients. Conclusion. Ovarian cancer survivors had an increased risk of type II diabetes compared with women in the general population. Risk was elevated only within the first year of cancer diagnosis, thus surveillance bias cannot be ruled out. Our findings suggest that the increased risk of type II diabetes does not persist beyond the first year after cancer diagnosis. Citation Format: Seungmin Kim, Kerry Rowe, John Snyder, Alison Fraser, Ken Smith, Vikrant G. Deshmukh, Michael Newman, Kimberley Herget, Chun-Pin Chang, Dominik Ose, Mary C. Playdon, David Gaffney, Mia Hashibe. Long-term diabetes risk among ovarian cancer survivors in a population-based cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5795.

Abstract 5797: Genitourinary disease risks among ovarian cancer survivors in a population-based cohort study

Abstract Background. While genitourinary complications during treatment for ovarian cancer are well known, long-term adverse outcomes in the growing population of ovarian cancer survivors have yet to be characterized. The aim of our study is to describe the incidence of genitourinary diseases among ovarian cancer survivors after ovarian cancer diagnosis, compared to the general female population. Methods. We identified a cohort of 1,270 ovarian cancer survivors diagnosed between 1996 and 2012 in the Utah Cancer Registry, and up to five cancer-free women were matched to ovarian cancer survivors on birth year and state from the Utah Population Database (N=5,286). Genitourinary disease diagnoses were identified with ICD-9 codes from electronic medical records and statewide healthcare facilities data. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) for genitourinary outcomes at 1 to &amp;lt;5 years after cancer diagnosis and 5+ years after cancer diagnosis with adjustment for potential confounders (e.g., race, baseline body mass index (BMI), and baseline Charlson Comorbidity Index (CCI)). Results. Urinary system disorders were diagnosed more frequently in ovarian cancer survivors compared to women without cancer (34.6% vs 19.3%, p-value &amp;lt;0.001) in years 1-5 of follow up (HR: 2.53, 95% CI: 2.12-3.01). More than 5 years after cancer diagnosis, ovarian cancer survivors had a higher risk of hydronephrosis compared to the general population (HR: 9.10, 95% CI: 4.29-19.33). Genital organ disorders were also more common among ovarian cancer survivors (22.0%) compared to women in the general population (16.3%; HR: 1.89, 95% CI: 1.57-2.27). The risk of pelvic peritoneal adhesions was highest 1-5 years after cancer diagnosis (HR: 16.59, 95% CI: 7.00-39.34) and persisted 5+ years after cancer diagnosis (HR: 8.88, 95% CI: 1.88-41.91). A higher risk of urinary system disorders among ovarian cancer patients was associated with advanced cancer stage (HRadvanced vs. localized: 3.11, 95% CI: 2.18-4.45), older age at cancer diagnosis (HR80+ vs. 18-49: 2.85, 95% CI: 1.62-5.01), and higher baseline CCI score (HR2+ vs. 0: 2.71, 95% CI: 1.84-3.99). The associations remained when we restricted analyses to ovarian cancer survivors with high-grade serous ovarian cancer. Conclusions. In this population-based cohort study, ovarian cancer survivors experienced increased risks of various genitourinary diseases for many years after cancer diagnosis. Understanding the multimorbidity trajectory for ovarian cancer survivors after cancer treatment is needed to ultimately improve clinical care after cancer diagnosis. The present results point to the importance of monitoring for genitourinary diseases among ovarian cancer survivors. Citation Format: Chun-Pin Chang, Yuji Chen, Brenna Blackburn, Sarah Abdelaziz, Kerry Rowe, John Snyder, Mark Dodson, Vikrant Deshmukh, Michael Newman, Joseph B. Stanford, Christina A. Porucznik, Jennifer Ose, Alison Fraser, Ken Smith, Jennifer Doherty, David Gaffney, Mia Hashibe. Genitourinary disease risks among ovarian cancer survivors in a population-based cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5797.

Abstract 5803: Cardiovascular disease risks in younger and older B-cell non-Hodgkin's lymphoma survivors

Abstract Introduction. Non-Hodgkin's lymphoma (NHL) is the fifth most common cancer in the United States. B-cell lymphoma accounts for 80-90% of NHL cases. Younger age at cancer diagnosis is associated with higher survival rates. However, younger cancer survivors may experience accelerated aging due to the cancer treatment that they undergo. The aim of this population-based study is to estimate long-term cardiovascular risk among younger and older adult NHL survivors compared to their respective general population cohorts. Methods. B-cell non-Hodgkin's lymphoma (B-NHL) survivors diagnosed from 1997 to 2015 in the Utah Cancer Registry were matched with up to five cancer-free individuals on birth year, sex, birth state, using the statewide Utah Population Database. Electronic medical records and statewide healthcare facility data were used to identify disease outcomes 5 years or more after cancer diagnosis. Cox Proportional Hazards models were used to estimate hazard ratios (HR). Test for heterogeneity was used to compare the HR for the older and younger cohorts. Results. There were 2,146 B-NHL survivors (1,284 diagnosed &amp;lt;65 years old and 862 diagnosed ≥65 years old) and 13,880 individuals from the general population ≥5 years after cancer diagnosis. Both younger and older B-NHL survivors had elevated risks for congestive heart failure, respectively (HRyounger = 1.65, 99% CI = 1.07-2.56; HRolder = 1.40, 99% CI = 1.01-1.96) compared to their respective general population cohorts. The younger B-NHL cohort had higher relative risks for chronic rheumatic disease of the heart valves (HRyounger = 2.87, 99% CI=1.64-5.02; HRolder=1.17, 99% CI=0.73-1.90; p-valueheterogeneity = 0.017), peri-; endo-; and myocarditis (HRyounger =2.26, 99%CI=1.34-3.79; HRolder = 0.80, 99% CI=0.46-1.39; p-value heterogeneity = 0.007), and cardiomyopathy (HRyounger=2.14, 99%CI=1.18-3.91; HRolder=0.93, 99%CI=0.51-1.72; p-valueheterogeneity= 0.056) than the older cohort. For other CVD outcomes, increased risks were observed in the younger B-NHL survivors and not in the older B-NHL survivors, but these differences were not statistically significant. Smoking and baseline obesity were major long-term risk factors of heart disease among younger B-NHL survivors. First course cancer treatment was not associated with cardiovascular disease risks ≥5 years after cancer diagnosis among B-NHL survivors. Conclusion. Elevated long-term risk for congestive heart failure was observed in B-NHL survivors compared to the general population. Younger B-NHL survivors had higher relative risks than older B-NHL survivors for chronic rheumatic heart disease, peri-; endo-; and myocarditis, and cardiomyopathy compared to their respective general population cohort groups. Although these increased disease risks suggest some early aging for young B-NHL survivors, most cardiovascular disease risks were not different between the two age groups. Citation Format: Krista Ocier, Sarah Abdelaziz, Seungmin Kim, Kerry Rowe, John Snyder, Vikrant Deshmukh, Michael Newman, Alison Fraser, Ken Smith, Kimberly Herget, Christy Porucznik, Kimberley Shoaf, Joseph Stanford, Catherine Lee, Mia Hashibe. Cardiovascular disease risks in younger and older B-cell non-Hodgkin's lymphoma survivors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5803.

Abstract A11: Neighborhood clustering of bladder cancer incidence in Utah: Analyzing census data linked to cancer records

Abstract Evaluating risk factors across the lifespan (using the life course perspective) is important when considering the role of environment on BCa risk. Spatial cluster detection methods offer unique opportunities to identify shared exposures of individuals with BCa on the local level and formulate hypotheses about the potential role of environmental exposures. This study tests for evidence of spatial clustering of BCa incidence based on neighborhoods defined as 1940 US Census enumeration districts (ED). Data were extracted from the Utah Population Database (UPDB). UPDB holds birth, death, historic US Census, and driver license records that allow tracking of an individual’s location across the lifespan. UPDB is linked to the Utah Cancer Registry, an original member of the Surveillance, Epidemiology, and End Results program. Incident BCa cases from 1966 to 2017 were identified in the UCR or by death records and linked to UPDB. We geocoded all 1940 US Census ED centroids in Utah using US Census maps and ArcGIS software. The cohort comprises all individuals age 0–40 years at the time of the 1940 Census (Ncohort=343,521). We excluded individuals with an absence of follow-up information (Nexcluded=82,726). Our final cohort size was 260,795 individuals who contributed 13,816,670 person-years. SatScan software was used to identify spatial clustering of EDs with high rates of BCa. BCa was diagnosed in 2,654 individuals during follow-up (rate=19.2 cases per 100,000 person-years). Approximately 78.4% of cases were male. Average follow-up time was 53 years (range 1-78 years). We identified a circular cluster of 1.54 kilometers in diameter containing 23 ED centroids in an urban area, with a rate of 32.7 cases per 100,000 person-years (relative risk = 1.73, p=0.0023). We found evidence of spatial clustering of BCa incidence in an urban area of Salt Lake City, Utah for individuals in early life (0-40 years) at the time of the 1940 US Census. Individuals residing in this shared space were significantly more likely to develop BCa later in life, with a 73% increase in the incidence rate. Shared space in this context is presumed to be a proxy for environmental exposures. Environmental exposures including arsenic in drinking water and exposure to carcinogenic chemicals are associated with bladder cancer incidence. While this study was hypothesis generating and did not test for contaminants directly, future studies would benefit from the inclusion of contamination data. Additionally, we were limited by the use of residential history at a single time point and lack of data on personal behaviors (e.g., smoking). Strengths of this study include large cohort size, long follow-up time, and ability to expand to an early census. A life course perspective on cancer incidence provides for innovative methods to explore the environmental contexts of disease. Citation Format: Claire L. Leiser, Marissa Taddie, Rebecca Richards-Steed, James A. VanDerslice, Brock O’Neil, Heidi A. Hanson. Neighborhood clustering of bladder cancer incidence in Utah: Analyzing census data linked to cancer records [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A11.

Abstract PR05: Fine particulate matter and mortality among pediatric, adolescent, and young adults with cancer

Abstract Background: Fine particulate matter air pollution (PM2.5) is associated with mortality in the adult population and in adults diagnosed with lung and breast cancer. The effect of PM2.5 on mortality in pediatric, adolescent, and young adults (AYA) diagnosed with cancer is unknown. We examine the association between PM2.5 and mortality among pediatric and AYAs diagnosed with cancer in Utah, a state with severe PM2.5 pollution. Methods: We identified 2,631 pediatric cancer patients aged 0 to 14 years and 14,575 AYA cancer patients aged 15 to 39 years diagnosed from 1986 to 2016. Patients were followed from first diagnosis date to five or ten years post-diagnosis, death, or emigration out of Utah as indicated by Utah Population Database records. We estimated average PM2.5 at each subject’s ZIP code at diagnosis from the first diagnosis date to the five- and ten-year follow-up dates, death, or emigration. We estimated the effect of five- and ten-year PM2.5 exposure on mortality at five and ten years post-diagnosis. Cox models controlled for parental education, sex, diagnosis year, and cancer stage/severity. Pediatric and AYA cancers were run in separate models. Pediatric cancers were stratified by International Classification of Childhood Cancer categories and AYA cancers were stratified by the WHO Classification for AYA cancers. Models were run for all-cause mortality and cancer-mortality, with noncancer deaths included as competing risks. Results: We found 571 (20%) deaths among pediatric patients and 3,064 (19.6%) deaths among AYA patients. Most deaths occurred within five years of diagnosis for both groups (83% and 67%, respectively). Cancer was the predominant cause of death among pediatric (94%) and AYA patients (92%). Pediatric patients were exposed to mean PM2.5 of 9.13 μg/m3 and AYA patients were exposed to a mean PM2.5 of 8.31 μg/m3. During five years of follow-up, we found significant associations between PM2.5 and all-cause and cancer mortality for pediatric central nervous system (CNS) patients (all-cause: 1.07 [95%CI: 1.01-1.13], cancer: 1.10 [1.04-1.17]). Among AYAs, we found that five-year PM2.5 exposure was associated with all-cause mortality and cancer-mortality among CNS (all-cause: 1.07 [1.03-1.12], cancer: 1.09 [1.04-1.14]) and carcinoma patients (all-cause: 1.03 [1.01-1.06], cancer: 1.04 [1.02-1.07]). During ten years of follow-up, PM2.5 had a significant association with all-cause and cancer-mortality among pediatric leukemia (all-cause: 1.09 [1.03-1.15], cancer: 1.09 [1.03-1.16]) and CNS patients (all-cause: 1.10 [1.05-1.15], cancer: 1.12 [1.06-1.17]). Among AYAs, ten-year PM2.5 was associated with all-cause and cancer-mortality among CNS (all-cause: 1.05 [1.02-1.09], cancer: 1.06 [1.03-1.10]), melanoma (all-cause: 1.07 [1.02-1.12], cancer: 1.08 [1.02-1.14]), and carcinoma patients (all-cause: 1.06 [1.04-1.08], cancer: 1.07 [1.05-1.09]). Conclusion: PM2.5 is associated with mortality among pediatric and AYA cancer patients. This abstract is also being presented as Poster A35. Citation Format: Judy Y. Ou, Heidi A. Hanson, Joemy M. Ramsay, Heydon Kaddas, C. Arden Pope, Claire L. Leiser, James A. VanDerslice, Anne C. Kirchhoff. Fine particulate matter and mortality among pediatric, adolescent, and young adults with cancer [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr PR05.

Germline mutation rates in young adults\xa0predict longevity and reproductive lifespan

Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d’Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. Subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21–3.56; p = 0.008; median survival difference = 4.7 years). Fertility analyses were restricted to women whose age at last birth (ALB) was ≥ 30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.

Low accuracy of self-reported family history of melanoma in high-risk patients.

Family history of melanoma is a major melanoma risk factor. However, self-reported family histories for some cancers, including melanoma, are commonly inaccurate. We used a unique database, the Utah Population Database (UPDB), as well as the Utah Cancer Registry to determine the accuracy of self-reported family history of melanoma in a large cohort of high-risk patients. Patient charts were reviewed and compared to records in the UPDB and the UCR to confirm personal and family history of melanoma in 1780 patients enrolled in a total body photography monitoring program. Self-reported family history of melanoma in first-degree relatives had an overall sensitivity of 71%, specificity of 79%, PPV of 31%, and NPV of 95%, with decreased accuracy (PPV) for second-degree relatives. A personal history of melanoma was the only factor significantly associated with accuracy in self-reported family history of melanoma. Patient age, sex, estimated nevus count, and number of prior personal melanomas were not significant predictors. Dermatologists should educate patients on the differences between melanomas, keratinocyte carcinomas, and pre-cancers. Confirming self-reported family history of melanoma may improve risk assessment for patients undergoing screening.

Colorectal cancer in the setting of pregnancy and familial risk.

Women are at risk of colorectal cancer (CRC) during pregnancy but this fact is underappreciated. We performed a population-based study to evaluate the rate, predictors, and familial risk for pregnancy associated CRC in Utah. All newly diagnosed cases of CRC between 1973 and 2014 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Of the 12,886 females diagnosed with CRC, 73 were diagnosed with CRC (0.57%) during the period of obstetric delivery/childbirth. Pregnancy associated CRC was diagnosed at a mean age of 31.9years, and cancers were less frequently located in the proximal colon compared with women with non-pregnancy associated CRC. First-degree relatives of cases with pregnancy associated CRC had a nearly threefold higher risk of CRC (OR, 2.76; 95% CI, 1.26-6.01) compared with relatives of CRC-free individuals. Of women diagnosed with CRC, less than 1% were diagnosed during or soon after obstetric delivery/childbirth. Relatives of these patients have a nearly threefold greater risk of CRC than those without a family history of CRC. These results provide physicians with data to guide the care of patients and their relatives with pregnancy associated CRC.

Harnessing Population Pedigree Data and Machine Learning Methods to Identify Patterns of Familial Bladder Cancer Risk.

Relatives of patients with bladder cancer have been shown to be at increased risk for kidney, lung, thyroid, and cervical cancer after correcting for smoking-related behaviors that may concentrate in some families. We demonstrate a novel approach to simultaneously assess risks for multiple cancers to identify distinct multicancer configurations (multiple different cancer types that cluster in relatives) surrounding patients with familial bladder cancer. This study takes advantage of a unique population-level data resource, the Utah Population Database (UPDB), containing vast genealogy and statewide cancer data. Familial risk is measured using standardized incidence risk (SIR) ratios that account for sex, age, birth cohort, and person-years of the pedigree members. We identify 1,023 families with a significantly higher bladder cancer rate than population controls (familial bladder cancer). Familial SIRs are then calculated across 25 cancer types, and a weighted Gower distance with K-medoids clustering is used to identify familial multicancer configurations (FMC). We found five FMCs, each exhibiting a different pattern of cancer aggregation. Of the 25 cancer types studied, kidney and prostate cancers were most commonly enriched in the familial bladder cancer clusters. Laryngeal, lung, stomach, acute lymphocytic leukemia, Hodgkin disease, soft-tissue carcinoma, esophageal, breast, lung, uterine, thyroid, and melanoma cancers were the other cancer types with increased incidence in familial bladder cancer families. This study identified five familial bladder cancer FMCs showing unique risk patterns for cancers of other organs, suggesting phenotypic heterogeneity familial bladder cancer. FMC configurations could permit better definitions of cancer phenotypes (subtypes or multicancer) for gene discovery and environmental risk factor studies.