Background: Emerging evidence suggests newborn screening analytes may yield insights into the etiologies of birth defects, yet no effort has evaluated associations between a range of newborn screening analytes and birth defects. Methods: This population-based study pooled statewide data on birth defects, birth certificates, and newborn screening analytes from Texas occurring between January 1, 2007 and December 31, 2009. Associations between a panel of thirty-six newborn screening analytes, collected by the statewide Texas Newborn Screening Program, and the presence of a birth defect, defined as at least one of 39 birth defects diagnoses recorded by the Texas Birth Defects Registry, were assessed using regression analysis. Findings: Of the 27,643 births identified, 20,205 had at least one of the 39 birth defects of interest (cases) as identified by the Texas Birth Defects Registry, while 7,438 did not have a birth defect (controls). Among 1,404 analyte-birth defect associations evaluated, 377 were significant in replication analysis. Analytes most consistently associated with birth defects included the phenylalanine/tyrosine ratio (N = 29 birth defects), tyrosine (N = 28 birth defects), and thyroxine (N = 25 birth defects). Birth defects most frequently associated with a range of analytes included gastroschisis (N = 29 analytes), several cardiovascular defects (N = 26 analytes), and spina bifida (N = 23 analytes). Conclusions: Several significant and novel associations were observed between newborn screening analytes and birth defects. While some findings could be consequences of the defects themselves or to the care provided to infants with these defects, these findings could help to elucidate mechanisms underlying the etiology of some birth defects.

Background and Aims: Genome‐wide association studies (GWAS) that were previously conducted in European and Asian cohorts have identified numerous genetic risk factors for hepatocellular carcinoma (HCC) and its precursors and risk factors. A polygenic risk score (PRS) composed of these key SNPs for HCC may be useful for risk stratification in clinical settings for U.S. patients with cirrhosis. Methods: Using genetic and clinical data from the Texas HCC Consortium cohort, we evaluated a weighted PRS constructed from 11 independent SNPs previously shown to be associated with advanced liver disease ( PNPLA3 – TM6SF2 – GCKR – HSD17B13 – GATAD2A – TRIB2 – PPP1R3B – CPN1 – ERLIN1 – APOE – MBOAT7 ). We used Fine‐Gray competing risk models to estimate hazard ratios (HR) and 95% confidence intervals (CI) to test the association between the PRS and HCC. Results: The 1888 patient cohort included non‐Hispanic White (NHW; 50.4%), non‐Hispanic Black (NHB; 18.5%), and Hispanic (28.6%) patients, and 116 developed incident HCC. Each unit increase in the PRS was associated with increasing risk of HCC (HR = 2.20; 95% CI (1.53, 3.18)). The 11‐SNP PRS was strongly associated with risk of HCC in NHW patients (HR = 2.53, 95% CI (1.65, 3.89)) but not among NHB and Hispanic patients. Similarly, the magnitude of the PRS effect on HCC risk differed by cirrhosis etiology with the strongest association for cirrhosis due to Hepatitis C (HR = 3.81, 95% CI (1.64, 8.82)). Conclusions: Our study shows that PRS is generally promising for HCC risk prediction; however, the current PRS that was derived from previous GWAS of primarily NHW and Asian patients is not robust over different groups, limiting their use for risk stratification in diverse populations with different etiologies.

Background: The impact of urban/rural residence on pediatric cancer incidence has not been well studied. Additionally, the impact of race/ethnicity on pediatric cancer incidence by urban/rural status has not been evaluated, which could inform our understanding of the roles of shared genetic and environmental causes of these malignancies. Methods: Using SEER18, we calculated pediatric cancer incidences for individuals diagnosed 2000-2018 by residence (urban/rural). Next we calculated incidence rate ratios (IRR) to evaluate the role of race/ethnicity on incidence stratified by urban vs. rural status. Results: See Table. Overall, most incidences were similar by residence, i.e., lower or equal in rural versus urban areas, except the rural group having significantly lower incidences of leukemias and germ cell tumors (GCTs). Additionally, the incidence of most pediatric cancers was consistently higher among NHW in both urban and rural areas. Yet, incidence of some cancers differed by urban/rural residence within race/ethnicity: retinoblastoma (NHB, Hispanic, and API); soft tissue sarcomas (NHB and AI/AN); hepatic tumors (AI/AN); and GCTs (API). Conclusions: In general, Hispanic, NHB, and AI/AN populations have similar incidence of pediatric cancers in urban or rural areas. These groups have some shared bio-geographical ancestry, suggesting a possible effect of genetics on risk. Further, differences in incidence by urban/rural residence within race/ethnicity suggest a possible role of environment for some cancers. Interestingly, for GCTs, NHB had a lower IRR in urban and rural areas, but Hispanic populations had a significantly higher IRR. This finding, consistent with a recent study in adults, suggest that African ancestry may confer a protective effect on risk of GCTs. Further, the GCT effect sizes were more protective in the rural group for each race/ethnicity group, suggesting the possible role of environmental factors and interactions of environment with ancestry. Citation Format: Priya B. Shetty, Philip J. Lupo, Michael E. Scheurer. Pediatric cancer incidence among racial/ethnic groups living in rural/urban areas of the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5223.

Background: Ependymoma is a malignancy of the neuroepithelium-derived ependyma that lines the spinal cord and ventricles of the brain, occurring most frequently in young children and older adults. Genetic susceptibility to ependymoma has proven difficult to assess due to disease rarity. Methods: We performed genome-wide association studies (GWAS) of 478 ependymoma patients and 4,841 disease-free controls of European ancestry. Ependymoma patients consisted of 117 children (<18 years old) with whole-genome sequencing (WGS), 142 children with genotyping, and 219 adults (≥18 years old) with genotyping. Genotyped samples were imputed using the 1,000 Genomes Project as the reference panel and underwent quality control filtering. The GWAS was performed separately by age group and technology (genotyped or WGS). GWAS variants were considered significant at P < 5 × 10−8. Results: Among pediatric subjects with WGS data, we identified a significant intronic variant in EDIL3 (rs149378, P = 1.9 × 10−8) and a nearly significant intronic variant in LHX4 (rs79008224, P = 7.2 × 10−8). In pediatric subjects with genotyped data, two significant intronic variants were detected: FAM149A (rs6852180, P = 1.8 × 10−8) and CYS1 (rs61052588, P = 3.0 × 10−8). Additionally, an intergenic variant near C1orf94 (rs1404350, P = 1.2 × 10−14) was highly significant. In genotyped adult subjects, a single variant was observed in KCNQ3 (rs79089725, P = 2.0 × 10−8). Conclusion: Our analysis represents one of the most extensive ependymoma-specific GWAS conducted to date. Several significant intronic variants were harbored in genes associated with cancer and neurological disease. Future studies are needed to investigate the role of these age-specific alterations in ependymoma pathogenesis.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. In the U.S., HCC incidence is highest among Hispanic populations. With the exception of well-known PNPLA3 variants, the genetic risk factors underlying HCC in Hispanic individuals, particularly rare germline variants, are largely unexplored. Methods: We performed whole-exome sequencing in 719 Hispanic Americans, including 455 HCC cases and 264 controls. We analyzed rare to low frequency, putatively deleterious variants in 86 genes previously implicated in HCC susceptibility. Genetic associations were assessed at single-variant, gene, and cumulative multi-variant burden levels using Fisher’s exact tests and weighted burden tests. Results: We identified 29 rare deleterious variants across 16 genes enriched in HCC cases compared with controls. Single-variant tests identified statistically robust associations in pathways related to lipids metabolism, TM6SF2 R138W, immune regulation, HLA-DRB1 W38X, and Wnt signaling pathway, WNT9A R375H. Exploratory analyses showed that TM6SF2 R138W was further enriched among cases with alcohol and metabolic dysfunction-associated steatotic liver disease. Gene-based burden tests revealed five associated genes, including TM6SF2 and HLA-DRB1. A strong dose-effect relationship was observed, with HCC risk increasing ~4-fold per candidate variant carried (odds ratio, 3.84; 95% confidence interval, 2.40–6.53). Conclusions: Rare deleterious germline variants across lipid metabolism and immune pathways contribute to increased HCC risk in Hispanic individuals. These findings provide a genetic framework for understanding HCC disparities and support future mechanistic and epidemiologic studies in this high-risk population.