Localized variation in ancestral admixture identifies pilocytic astrocytoma risk loci among Latino children

Li, Shaobo; Chiang, Charleston W.K.; Myint, Swe Swe; Arroyo, Katti; Chan, Tsz Fung; Morimoto, Libby; Metayer, Catherine; Smith, Adam J. de; Walsh, Kyle M.

doi:10.1371/journal.pgen.1010388

Cited by 3 publications

(1 citation statement)

References 38 publications

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“…Local ancestry inference was first performed on CCRLP LAT cases and controls using RFMix, 35 using a reference panel consisting of 671 non-Finnish European individuals for European ancestry, 716 African individuals for African-ancestry, and 94 Admixed American individuals (7 Colombian, 12 Karitianan, 14 Mayan, 4 Mexican in Los Angeles, 37 Peruvian in Lima, Peru, 12 Pima, and 8 Surui) for Indigenous American (IA) ancestry from gnomAD v3.1 release, 36 as previously identified to be enriched with indigenous ancestry. 37 We then summed the local ancestry estimates across the genome to derive the global ancestry estimates. We stratified Latino individuals into three tertiles of global European ancestry, and in each group evaluated the predictive performance of the best PRS model for NLW_NLW strategy.…”

Section: Methodsmentioning

confidence: 99%

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos

Jeon,

Lo,

Morimoto

et al. 2023

Human Genetics and Genomics Advances

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Section: Methodsmentioning

confidence: 99%

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos

Jeon,

Lo,

Morimoto

et al. 2023

Human Genetics and Genomics Advances

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Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos

Jeon

Morimoto

et al. 2023

Preprint

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The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWAS), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study we constructed and evaluated genomic PRS models based on either non-Latino white (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR2 = 0.086 +/- 0.023 in NLW vs. 0.060 +/- 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR2 = 0.116 +/- 0.026) or multi-ancestry samples (PseudoR2 = 0.131 +/- 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR2 = 0.166 +/- 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWAS may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligo-genic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.

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Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors from the PBTA and PNOC

Corbett,

Gullickson,

Geng

et al. 2024

Preprint

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BackgroundCentral nervous system (CNS) tumors lead to cancer-related mortality in children. Genetic ancestry-associated cancer prevalence and outcomes have been studied, but is limited.MethodsWe performed genetic ancestry prediction in 1,484 pediatric patients with paired normal and tumor whole genome sequencing from the Open Pediatric Cancer (OpenPedCan) project to evaluate the influence of reported race and ethnicity and ancestry-based genetic superpopulations on tumor histology, molecular subtype, survival, and treatment.ResultsPredicted superpopulations included African (AFR, N=155), Admixed American (AMR, N=224), East Asian (EAS, N=67), European (EUR, N=995), and South Asian (SAS, N=43). Reported race and ethnicity and ancestry-based genetic superpopulations were non-randomly associated. Patients with an atypical teratoid rhabdoid tumor (ATRT),MYCsubtype or meningioma were enriched for AFR ancestry. Patients of AMR ancestry withKIAA1549::BRAFfusion-positive low-grade glioma (LGG) had tumors enriched for rare fusion breakpoints, lesser extent of surgical resection, and worse event-free survival (EFS). Non-EUR and AMR patients with germ cell tumors or SHH-activated medulloblastoma exhibited worse EFS relative to EUR patients, and patients of AFR ancestry with LGG or ependymoma had worse overall survival compared to EUR patients. We observed higher frequency of clinical trial enrollment among AMR patients across tumor histologies, but increased utilization of photon versus proton radiation relative to other superpopulations.ConclusionsGenetic ancestry-associated disparities exist across pediatric CNS tumor histological and molecular subtypes. Further investigation into genetic and socioeconomic factors contributing to these observed inequities is needed.Key PointsDistinct associations of genetic ancestry-based superpopulations exist within pediatric CNS tumor histologic and molecular subtypes and correlate with survival outcomes and treatment.Importance of the StudyThis work provides critical insight on the impact of reported race and ethnicity and genetic-based ancestry superpopulations on nearly 1,500 pediatric patients with CNS tumors who had matched normal and tumor sequencing performed. We identify novel associations between ancestry superpopulations and tumor histology, molecular subtypes, and treatments received. Here, we begin to inform on the contributions of social constructs of race and ethnicity and tumor characteristics that are enriched among genetic-based ancestry superpopulations on clinical outcomes of pediatric patients with CNS tumors. Our findings indicate that potential social and genetic risk stratifications exist for pediatric CNS tumors and warrant further investigation to ensure equitable clinical outcomes for all patients.

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Localized variation in ancestral admixture identifies pilocytic astrocytoma risk loci among Latino children

Cited by 3 publications

References 38 publications

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos

Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos

Genetic ancestry superpopulations show distinct prevalence and outcomes across pediatric central nervous system tumors from the PBTA and PNOC

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