Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2025
Multiancestry Transcriptome-Wide Association Study Identifies Candidate Genes Associated with Hepatoblastoma.
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Xie Tiankai, Sorenson Josey C, Spector Logan G, Pankratz Nathan, Huang R Stephanie, Hiyama Eiso, Poynter Jenny N, Tomlinson Gail E, Armengol Carolina, Kappler Roland, Scheurer Michael E, Roman Eve, Castellano Aurora, Grotzer Michael A, Ziegler David S, Basu Saonli, Marcotte Erin L, Yang Tianzhong
Аннотация
BACKGROUND: Hepatoblastoma (HB) is a rare embryonal liver tumor, with an increasing global incidence that underscores the need to understand its genetic etiology.
METHODS: Utilizing the ancestry-matched expression quantitative loci data, we performed a HB transcriptome-wide association study (TWAS) on 4,539 Europeans, 1,047 Latinos, and 378 African Americans (∼1:10 case-control ratio). We conducted a meta-analysis of multiancestry transcriptome-wide analysis (METRO), followed by METRO-Egger sensitivity analysis and ancestry-specific gene set enrichment analyses. We further explored genes with additional evidence gathered from independent cohorts and databases.
RESULTS: Across the three ancestries, the discovered genes shared the same effect direction across ancestries. A meta-analysis of the three ancestries identified 28 genes significantly associated with HB risk, and 15 were nominally significant for at least two ancestries. Our post-TWAS analyses highlighted 8 genes among these 28, including OXER1 (meta-analysis P value = 7.34 × 10-6), FADS1 (P value = 4.01 × 10-6), and UGDH (P value = 5.29 × 10-8), which were expressed in fetal liver hepatoblast cells and were differentially expressed in tumor and normal tissues in an independent Japanese HB study (P values = 2.61 × 10-13, 3.62 × 10-3, and 1.95 × 10-9, respectively).
CONCLUSIONS: We pinpointed eight potential genes associated with HB using data from an ongoing multiancestry genome-wide association study.
IMPACT: We conducted the largest HB TWAS to date, prompting further exploration of genes.
METHODS: Utilizing the ancestry-matched expression quantitative loci data, we performed a HB transcriptome-wide association study (TWAS) on 4,539 Europeans, 1,047 Latinos, and 378 African Americans (∼1:10 case-control ratio). We conducted a meta-analysis of multiancestry transcriptome-wide analysis (METRO), followed by METRO-Egger sensitivity analysis and ancestry-specific gene set enrichment analyses. We further explored genes with additional evidence gathered from independent cohorts and databases.
RESULTS: Across the three ancestries, the discovered genes shared the same effect direction across ancestries. A meta-analysis of the three ancestries identified 28 genes significantly associated with HB risk, and 15 were nominally significant for at least two ancestries. Our post-TWAS analyses highlighted 8 genes among these 28, including OXER1 (meta-analysis P value = 7.34 × 10-6), FADS1 (P value = 4.01 × 10-6), and UGDH (P value = 5.29 × 10-8), which were expressed in fetal liver hepatoblast cells and were differentially expressed in tumor and normal tissues in an independent Japanese HB study (P values = 2.61 × 10-13, 3.62 × 10-3, and 1.95 × 10-9, respectively).
CONCLUSIONS: We pinpointed eight potential genes associated with HB using data from an ongoing multiancestry genome-wide association study.
IMPACT: We conducted the largest HB TWAS to date, prompting further exploration of genes.