2025 Sequencing Strategies for Population and Cancer Epidemiology Studies (SeqSPACE)

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# Created User IP address First Name Middle Initial Last Name Degree(s) Position/Title/Career Status Organization Email Abstract Title Abstract Summary Operations
8 Fri, 09/05/2025 - 13:46 Anonymous 10.208.24.84 Cheng Peng Sc.D. Assistant Professor Brigham and Women's Hospital and Harvard Medical School recpe@channing.harvard.edu Whole exome-sequencing based COSMIC triple negative breast tumor mutational signatures in the 4 U.S. based prospective cohort studies Tumor whole exome sequencing provides a systemic readout of the genetic architecture of the tumor. The Catalogue Of Somatic Mutations In Cancer (COSMIC) signatures capture the different underlying mutational processes that may arise from different exposures (exogenous or endogenous). We profiled tumor whole exome-sequencing among 234 triple-negative breast cancer patients from 4 U.S. based prospective cohorts (Nurses’ Health Study / NHS and NHS2 [n=151], Cancer Prevention Study /CPS II and 3 [n=83]). We compared key participant characteristics, the presence and distribution of selected tumor mutational signatures for TNBC cases identified in NHS/NHS2 and CPSII/3. Mean age at diagnosis is 59 for both NHS and NHS2 (range=36-86) and CPSII and CPS3 (range=31-85). Majority of TNBC cases had stage I or II cancers at diagnosis (90% for NHS and NHS2, 83% for CPSII and CPS3, percentage calculated from none-missing samples). For many signatures (e.g., SBS1, SBS2), we observed comparable proportions of samples with somatic mutations contributing to the signatures in NHS and NHS2 and CPSII and CPS3. As a next step, we will examine fruits and vegetable intake, dietary and circulating carotenoids, which are important sources of anti-oxidants, in relation to tumor somatic mutational patterns among TNBC cases in the 4 cohorts.
7 Fri, 09/05/2025 - 12:41 Anonymous 10.208.24.84 Austin Hammermeister Suger MS 4th year Epidemiology Ph.D. student / Mr. / Graduate Student Lindström Group / Department of Epidemiology / University of Washington School of Public Health hammea2@uw.edu Rare genetic variant contributions to multiple cancers Purpose: While previous studies have assessed associations between rare genetic variation and cancer, they have mostly 1) examined a limited number of cancer types and 2) included only European genetic ancestry individuals. The generation sequencing data by large population-based biobanks enables more comprehensive examinations of the relationships between rare genetic variants and multiple cancers across populations. We assessed associations between rare genetic variants and over 70 cancer types using sequencing data from 431,961 and 297,508 multi-ancestry participants from the UK Biobank (UKB) and All of Us Research Program (AoU) cohorts, respectively. Methods: We used three approaches to characterize the influences of rare coding variants on risk for various cancers. First, we used generalized linear mixed models to conduct gene-based burden tests and single variant tests for over 70 individual cancers and groups of cancers in the full multi-ancestry UKB and AoU cohorts. Second, we estimated the contributions of rare coding variants to breast, colorectal, and prostate cancer heritability in genetic ancestry-stratified groups in the UKB and AoU cohorts using methods that generate both aggregate and gene-level heritability estimates. Third, we developed polygenic scores (PGS) that integrated existing common variant PGS and rare variant effects for breast, colorectal, and prostate cancers and evaluated the performance of these PGS across genetic ancestry groups in the UKB and AoU cohorts. Results: We identified 15 genes (ASXL1, ATM, BRCA1, BRCA2, CDKN2A, CHEK2, DNMT3A, MLH1, PALB2, POT1, PPM1D, RTEL1, SAMHD1, TET2, and TP53) that showed associations across a range of the individual cancer types tested. We estimated small heritability contributions from rare variants that were enriched in known cancer risk genes. Conclusions: Our results suggest that utilizing the expansive sequencing and cancer diagnosis data in large population-based biobanks could expand our understanding of the role of rare genetic variants in cancer risk.
6 Thu, 09/04/2025 - 18:34 Anonymous 10.208.24.100 Harriett Fuller Ph.D. Postdoctoral research fellow Darst Lab/ Public Health Sciences Division/ Fred Hutchinson Cancer Center hfuller@fredhutch.org A cross-population two-sample Mendelian randomization study of circulating metabolomics and prostate cancer risk. Prostate cancer (PCa) is the 2nd most common cancer in men, with African American (AFR) men experiencing the highest disease incidence. Metabolomic dysregulation likely contributes to pathogenesis, however epidemiological evidence is heterogenous and limited in diverse populations. Herein, we conducted a two-sample Mendelian Randomization (MR) analyses, facilitated by imputation to dense sequencing resources, to assess causal relationships between serum metabolites and PCa risk in AFR, European (EUR) and Hispanic (HIS) populations.MR was performed using GWAS summary statistics (imputed to TOPMed) from the Atherosclerosis Risk in Communities (ARIC) cohort (NMetabolites=250, NEUR=1,498, NAFR=1,740) and the Hispanic Community Health Study/ Study of Latinos (HCHS/SOL) cohort (NMetabolites=711, NHIS=3,166). Metabolites were quantified by untargeted mass spectroscopy (Metabolon). PCa GWAS summary statistics (imputed to 1KGP) were obtained from PRACTICAL (AFR=10,368/10,986, EUR=85,554/91, HIS=3,931/26,405 cases/controls). Genome-wide significant (P<5x10-8) and independent (R2<0.2 in TopLD) SNPs were included in instruments. MR results were meta-analyzed across populations. The strength of MR evidence was evaluated utilizing newly developed criteria for metabolites with a false discovery rate (FDR) < 0.10. Fifty metabolites significantly associated with PCa risk in population-specific or cross-population analyses. Based on our criteria, fourteen metabolites had strong MR evidence, and were followed up in additional analyses. We found that 10 of these metabolites were novel associations, three were drug-modifiable and six were dietary modifiable. The fatty acid hexadecanedioate was the only metabolite associated with PCa risk in AFR (OR=1.10, 95% CI=1.05-1.16, Padj=0.02) and exhibited evidence of colocalization for rs28864441. Hexadecanedioate was not associated with PCa risk in EURs or HISs. This large-scale MR study provides evidence of causal associations between serum metabolites and PCa within and across populations and highlights the role lipids, nucleotides and amino acids in PCa development. Underlining biological mechanisms and the clinical utility of identified metabolites as PCa biomarkers should be evaluated in diverse populations.
5 Wed, 09/03/2025 - 15:21 Anonymous 10.208.24.230 Monica A. Wagner Ph.D Assistant Professor (Tenure Track) Case Western Reserve University maw269@case.edu Transcriptomic Profiling of Socioeconomic Stratification in Oropharyngeal Squamous Cell Carcinoma Socioeconomic disadvantage is increasingly recognized as a contributor to differences in cancer outcomes, yet its biological mechanisms remain poorly understood. To explore the molecular impact of social context, we performed bulk RNA sequencing on whole blood samples from individuals diagnosed with oropharyngeal squamous cell carcinoma, collected either prior to radiation or more than one-year post-treatment. Participants were stratified by Area Deprivation Index (ADI), a validated measure of neighborhood-level socioeconomic disadvantage ranging from 1 to 100, with higher scores indicating greater disadvantage.
Using the DESeq2 pipeline, we modeled differential gene expression between individuals with high ADI (80-100; n=12) and low ADI (1-40; n=11). Genes were considered significant using a raw p-value threshold of < 0.05, chosen to enhance sensitivity in this exploratory, hypothesis-generating analysis. While adjusted p-values are standard for controlling false discovery rates, our use of unadjusted p-values reflects the preliminary nature of the dataset and supports future validation efforts.
This approach revealed distinct gene expression profiles between ADI-high and ADI-low individuals, with notable differences in genes involved in oxidative stress (GPX1), immune regulation (PF4, TGFB1I1), and cellular signaling (FSTL1, TREML1). These findings suggest that individuals from socioeconomically disadvantaged neighborhoods may exhibit systemic biological alterations that influence disease progression, immune response, and treatment outcomes,
Peripheral blood offers a practical biospecimen for capturing circulating immune and inflammatory signals, providing insight into the systemic effects of social determinants of health. This study demonstrates the feasibility of integrating ADI into RNA-seq workflows to uncover biologically meaningful differences in cancer populations and highlights a scalable approach for investigating the intersection of social context and molecular biology in head and neck cancer.
4 Wed, 08/27/2025 - 00:06 Anonymous 10.208.28.36 Katherine Anne Lawson-Michod Ph.D. MPH Postdoctoral Fellow Fred Hutchinson Cancer Center klawsonm@fredhutch.org Homologous recombination deficiency and survival in ovarian high-grade serous carcinoma by self-reported race Survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) is worse for Black individuals compared to White individuals. Current understanding of HGSC molecular heterogeneity, including homologous recombination deficiency (HRD)—the most common etiologic pathway—is based largely on the evaluation of tumors from White patients. We leveraged newly generated whole-exome sequencing and existing RNASeq from 272 Black individuals with HGSC to identify significantly mutated genes, mutational signatures, and HRD features. We evaluated the reliability of our data by comparing to the Cancer Genome Atlas and confirmed our findings by comparing the data from Black patients with those from 123 White patients with identical tissue collection and processing. Finally, we incorporated epidemiologic data to annotate variants of uncertain significance (VUS) and assess whether population differences in HRD contribute to differences in survival. Despite technical differences, mutations and variant classifications for major HGSC genes were nearly identical across populations. However, de novo analysis identified novel significantly mutated genes, including the oncogene KRAS and a potential tumor suppressor OBSCN in Black patients. We also observed that a greater proportion of variants in homologous recombination genes were unannotated/VUS among Black individuals; however, these variants correlated with HRD scarring and a family history of breast or ovarian cancer suggesting some may be pathogenic. HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals. Overall, most HGSC tumor features are similar across Black and White individuals with HGSC, and it is unlikely that population differences in tumor features explain survival differences. Still, clinically relevant differences exist including a higher prevalence of certain tumor suppressor genes and a higher proportion of VUS among Black individuals which may hinder referral to care and contribute to worse outcomes. These findings underscore the need for diverse representation in genomics research.
3 Thu, 08/07/2025 - 13:23 Anonymous 10.208.24.35 Jing Dong PhD Assistant Professor Medical College of Wisconsin jidong@mcw.edu Leveraging Mitochondrial Genome to Predict Posttransplant Outcomes in Patients with Myelodysplastic Syndromes Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a propensity to progress to acute myeloid leukemia in approximately 30% of patients. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for MDS. However, post-transplant mortality remains high, primarily due to disease relapse and transplant-related complications. Currently available prognostic models for MDS in the HCT setting (e.g., IPSS-R) rely exclusively on clinical and hematologic parameters, with no incorporation of genetic information. As a result, they are limited in their ability to accurately predict transplant outcomes. Novel predictive biomarkers are urgently needed to identify patients most likely to benefit from allo-HCT and to inform risk-adapted treatment strategies. Mitochondria—the "powerhouses" of the cell—play critical roles in stem cell homeostasis, heme biosynthesis, iron metabolism, and immune regulation. To investigate the prognostic significance of mitochondrial DNA (mtDNA) variation, we performed whole-genome sequencing (WGS) on 494 MDS patients and their matched donors enrolled through the Center for International Blood and Marrow Transplant Research (CIBMTR). Analysis of both recipient and donor mtDNA genomes revealed that a higher burden of mtDNA variants was significantly associated with adverse post-HCT outcomes. Gene-based analyses identified variants in MT-CYB, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, and MT-tRNA as independent predictors of overall survival (OS), relapse-free survival (RFS), relapse, and/or transplant-related mortality (TRM). Furthermore, we applied random survival forest models and demonstrated that incorporating mtDNA variant data significantly improved the predictive performance of the IPSS-R model across all major transplant outcomes (OS, RFS, relapse, and TRM). To explore the potential mechanisms underlying these associations, we conducted computational structural genomics analyses of variants in mitochondrial complex I genes. Preliminary findings suggest that the adverse prognostic effects of these mtDNA variants may result from their deleterious impact on mitochondrial respiration and function.
2 Thu, 07/24/2025 - 13:42 Anonymous 10.208.24.46 Fei Chen Ph.D. Assistant Professor University of Southern California feic@usc.edu Pathogenic variants in cancer predisposition genes and risk of prostate cancer in men of African ancestry Background: The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) has not been well-defined in large populations of African ancestry.
Methods: In 7,176 PCa cases and 4,873 controls from seven countries in North America and Africa, we examined the association of PVs in 37 cancer predisposition genes with risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were included in the estimation of lifetime absolute risk based on family history of PCa, polygenic risk score (PRS), and carrier status of PVs.
Key Findings and Limitations: PVs in ATM, BRCA2, CHEK2, HOXB13, and PALB2 were found in 4% of aggressive or metastatic PCa and were significantly associated with an increased risk of aggressive PCa (odds ratios [ORs] 2.18-5.96, P<0.05). Depending on PV carrier status of these genes, PRS, and family history, there were substantial gradients in lifetime absolute risk of overall (3.0-74%), aggressive (0.6-41%), and metastatic (0.2-37%) PCa. Compared to men with average risk, the lifetime risks of overall, aggressive, and metastatic PCa were 7, 18, and 34 times, respectively, among PV carriers with a positive PCa family history in the 90th percentile of PRS. Given that the aggressive and metastatic PCa were over-sampled in this study, the generalizability of the associated risk estimates to a screening cohort needs further validation.
Conclusions and Clinical Implications: Our findings provided additional evidence that more refined estimates of PCa risk could be obtained by combining PRS, PV carrier status, and family history in risk prediction models. The wide range of PCa risk observed among African ancestry men in our study supports future prospective studies in the development of risk-stratified cancer screening programs based on an individual’s risk, for the identification of high-risk individuals that may benefit from screening at an earlier age.