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
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.