*Result*: Inferring germline pharmacogenomics from tumor transcriptome.
Title:
Inferring germline pharmacogenomics from tumor transcriptome.
Authors:
Yang W; Department of Pharmacy and Pharmaceutical Sciences., Wu G; Center for Applied Bioinformatics., Klco JM; Department of Pathology., Nichols KE; Department of Oncology., Jeha S; Department of Oncology.; Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee., Inaba H; Department of Oncology., Pui CH; Department of Pathology.; Department of Oncology.; Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee., Bhakta N; Department of Oncology.; Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee., Broeckel U; RPRD Diagnostics LLC, Milwaukee, Wisconsin, USA., Yang JJ; Department of Pharmacy and Pharmaceutical Sciences.; Department of Oncology., Haidar CE; Department of Pharmacy and Pharmaceutical Sciences.
Source:
Pharmacogenetics and genomics [Pharmacogenet Genomics] 2026 Jan 01; Vol. 36 (1), pp. 1-8. Date of Electronic Publication: 2025 Sep 25.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 101231005 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1744-6880 (Electronic) Linking ISSN: 17446872 NLM ISO Abbreviation: Pharmacogenet Genomics Subsets: MEDLINE
Imprint Name(s):
Original Publication: Hagerstown, MD : Lippincott Williams & Wilkins, c2005-
MeSH Terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma*/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/pathology , Transcriptome*/genetics , Pharmacogenetics*/methods, Methyltransferases/genetics ; Pyrophosphatases/genetics ; Germ Cells/metabolism ; Pharmacogenomic Testing/methods ; Humans ; Male ; Child ; Female ; Child, Preschool ; Germ-Line Mutation ; Infant ; Whole Genome Sequencing ; Adolescent ; Genotype ; Nudix Hydrolases
References:
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Relling MV, Klein TE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Caudle KE. The clinical pharmacogenetics implementation consortium: 10 years later. Clin Pharmacol Ther. 2020; 107:171–175.
Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009; 360:2730–2741.
Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, et al. Improved CNS control of childhood acute lymphoblastic leukemia without cranial irradiation: St Jude Total Therapy Study 16. J Clin Oncol. 2019; 37:3377–3391.
Karol SE, Pei D, Smith CA, Liu Y, Yang W, Kornegay NM, et al. Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy. Haematologica. 2022; 107:371–380.
Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999; 91:2001–2008.
Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015; 33:1235–1242.
Robinson KM, Yang W, Haidar CE, Hankins JS, Jay DW, Kornegay N, et al. Concordance between glucose-6-phosphate dehydrogenase (G6PD) genotype and phenotype and rasburicase use in patients with hematologic malignancies. Pharmacogenomics J. 2019; 19:305–314.
Hicks JK, Crews KR, Flynn P, Haidar CE, Daniels CC, Yang W, et al. Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes. Pharmacogenomics. 2014; 15:1065–1078.
Hoffman JM, Haidar CE, Wilkinson MR, Crews KR, Baker DK, Kornegay NM, et al. PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics. Am J Med Genet C Semin Med Genet. 2014; 166C:45–55.
Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, et al. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat Genet. 2022; 54:1376–1389.
Lee SHR, Antillon-Klussmann F, Pei D, Yang W, Roberts KG, Li Z, et al. Association of genetic ancestry with the molecular subtypes and prognosis of childhood acute lymphoblastic leukemia. JAMA Oncol. 2022; 8:354.
Newman S, Nakitandwe J, Kesserwan CA, Azzato EM, Wheeler DA, Rusch M, et al. Genomes for kids: the scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discov. 2021; 11:3008–3027.
McLeod C, Gout AM, Zhou X, Thrasher A, Rahbarinia D, Brady SW, et al. St. Jude Cloud: a pediatric cancer genomic data-sharing ecosystem. Cancer Discov. 2021; 11:1082–1099.
Li H, Ruan J, Durbin R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 2008; 18:1851–1858.
Chen X, Gupta P, Wang J, Nakitandwe J, Roberts K, Dalton JD, et al. CONSERTING: integrating copy-number analysis with structural-variation detection. Nat Methods. 2015; 12:527–530.
Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011; 27:2987–2993.
Poplin R, Ruano-Rubio V, DePristo MA, Fennell TJ, Carneiro MO, Auwera GAV der, et al. Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv; 2018. pp. 201178. https://www.biorxiv.org/content/10.1101/201178v3 . [Accessed 1 July 2024].
Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019; 105:1095–1105.
Geck RC, Powell NR, Dunham MJ. Functional interpretation, cataloging, and analysis of 1,341 glucose-6-phosphate dehydrogenase variants. Am J Hum Genet. 2023; 110:228–239.
Meeting report of the technical consultation to review the classification of glucose-6-phosphate dehydrogenase (G6PD). https://www.who.int/publications/m/item/WHO-UCN-GMP-MPAG-2022.01 . [Accessed 3 March 2024].
Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther. 2018; 103:210–216.
Relling MV, Klein TE, Gammal RS, Whirl-Carrillo M, Hoffman JM, Caudle KE. The clinical pharmacogenetics implementation consortium: 10 years later. Clin Pharmacol Ther. 2020; 107:171–175.
Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009; 360:2730–2741.
Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, et al. Improved CNS control of childhood acute lymphoblastic leukemia without cranial irradiation: St Jude Total Therapy Study 16. J Clin Oncol. 2019; 37:3377–3391.
Karol SE, Pei D, Smith CA, Liu Y, Yang W, Kornegay NM, et al. Comprehensive analysis of dose intensity of acute lymphoblastic leukemia chemotherapy. Haematologica. 2022; 107:371–380.
Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999; 91:2001–2008.
Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015; 33:1235–1242.
Robinson KM, Yang W, Haidar CE, Hankins JS, Jay DW, Kornegay N, et al. Concordance between glucose-6-phosphate dehydrogenase (G6PD) genotype and phenotype and rasburicase use in patients with hematologic malignancies. Pharmacogenomics J. 2019; 19:305–314.
Hicks JK, Crews KR, Flynn P, Haidar CE, Daniels CC, Yang W, et al. Voriconazole plasma concentrations in immunocompromised pediatric patients vary by CYP2C19 diplotypes. Pharmacogenomics. 2014; 15:1065–1078.
Hoffman JM, Haidar CE, Wilkinson MR, Crews KR, Baker DK, Kornegay NM, et al. PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics. Am J Med Genet C Semin Med Genet. 2014; 166C:45–55.
Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, et al. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat Genet. 2022; 54:1376–1389.
Lee SHR, Antillon-Klussmann F, Pei D, Yang W, Roberts KG, Li Z, et al. Association of genetic ancestry with the molecular subtypes and prognosis of childhood acute lymphoblastic leukemia. JAMA Oncol. 2022; 8:354.
Newman S, Nakitandwe J, Kesserwan CA, Azzato EM, Wheeler DA, Rusch M, et al. Genomes for kids: the scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discov. 2021; 11:3008–3027.
McLeod C, Gout AM, Zhou X, Thrasher A, Rahbarinia D, Brady SW, et al. St. Jude Cloud: a pediatric cancer genomic data-sharing ecosystem. Cancer Discov. 2021; 11:1082–1099.
Li H, Ruan J, Durbin R. Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 2008; 18:1851–1858.
Chen X, Gupta P, Wang J, Nakitandwe J, Roberts K, Dalton JD, et al. CONSERTING: integrating copy-number analysis with structural-variation detection. Nat Methods. 2015; 12:527–530.
Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011; 27:2987–2993.
Poplin R, Ruano-Rubio V, DePristo MA, Fennell TJ, Carneiro MO, Auwera GAV der, et al. Scaling accurate genetic variant discovery to tens of thousands of samples. bioRxiv; 2018. pp. 201178. https://www.biorxiv.org/content/10.1101/201178v3 . [Accessed 1 July 2024].
Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, et al. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. 2019; 105:1095–1105.
Geck RC, Powell NR, Dunham MJ. Functional interpretation, cataloging, and analysis of 1,341 glucose-6-phosphate dehydrogenase variants. Am J Hum Genet. 2023; 110:228–239.
Meeting report of the technical consultation to review the classification of glucose-6-phosphate dehydrogenase (G6PD). https://www.who.int/publications/m/item/WHO-UCN-GMP-MPAG-2022.01 . [Accessed 3 March 2024].
Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther. 2018; 103:210–216.
Grant Information:
5P30CA021765-39 National Institute of Health (NIH)
Contributed Indexing:
Keywords: leukemia; pharmacogenetics; pharmacogenomics; sequencing; transcriptome
Substance Nomenclature:
EC 2.1.1.- (Methyltransferases)
EC 3.6.1.- (Pyrophosphatases)
EC 2.6.1.- (NUDT15 protein, human)
EC 2.1.1.67 (TPMT protein, human)
EC 3.6.1.- (Nudix Hydrolases)
EC 3.6.1.- (Pyrophosphatases)
EC 2.6.1.- (NUDT15 protein, human)
EC 2.1.1.67 (TPMT protein, human)
EC 3.6.1.- (Nudix Hydrolases)
Entry Date(s):
Date Created: 20250925 Date Completed: 20251103 Latest Revision: 20260127
Update Code:
20260130
DOI:
10.1097/FPC.0000000000000576
PMID:
40995674
Database:
MEDLINE
*Further Information*
*Objectives: Pharmacogenomic testing is rapidly becoming the standard of care in treating pediatric acute lymphoblastic leukemia (ALL). Risk classification of ALL can be performed through whole transcriptome sequencing (WTS) of diagnostic tumor samples. We evaluated the feasibility of inferring germline pharmacogenomic genotypes from the tumor transcriptome in ALL.
Methods: Transcriptome and paired tumor-germline genome sequencing data were collected from clinical testing at St. Jude Children's Research Hospital. Genotypes for pharmacogenes that are actionable for medications used in the management of pediatric ALL ( TPMT, NUDT15 , and G6PD ) were determined using a rule-based algorithm from transcriptome data. WTS-derived genotype calls were compared with germline genotypes obtained from whole genome sequencing (WGS) and clinical genotyping assays.
Results: Among 650 patients with ALL, 36 (5.5%) patients had somatic copy number loss on chromosomes 6, 13, or X, where TPMT , NUDT15 , and G6PD are located, respectively. For the remaining 614 patients, WTS provided thiopurine dosing guidance by calling both TPMT and NUDT15 diplotypes in 545 patients (83.8%). For G6PD , accurate genotyping was called for 367 male patients. We observed a greater than 99% concordance between tumor WTS and germline WGS diplotypes for all three genes.
Conclusion: The leukemia transcriptome can be used to provide accurate genotyping calls for select germline pharmacogenes actionable in the treatment of pediatric ALL.
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