Real-world evaluation of universal germline screening for cancer treatment-relevant pharmacogenes

Megan L. Hutchcraft, Nan Lin, Shulin Zhang, Catherine Sears, Kyle Zachloski, Elizabeth A. Belcher, Eric B. Durbin, John L. Villano, Michael J. Cavnar, Susanne M. Arnold, Frederick R. Ueland, Jill M. Kolesar

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


The purpose of this study was to determine the frequency of clinically actionable treat-ment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-can-cer agents and associated outcomes. This observational study evaluated 291 patients with cancer. More than 90% carried any clinically relevant pharmacogenetic variant. At least one disease-rele-vant variant impacting anti-cancer agents was identified in 26.5% (77/291). Nine patients with tox-icity-associated pharmacogenomic variants were treated with a relevant medication: seven UGT1A1 intermediate metabolizers were treated with irinotecan, one intermediate DPYD metabo-lizer was treated with 5-fluorouracil, and one TPMT poor metabolizer was treated with mercapto-purine. These individuals were more likely to experience treatment-associated toxicities than their wild-type counterparts (p = 0.0567). One UGT1A1 heterozygote died after a single dose of irinotecan due to irinotecan-related adverse effects. Identifying germline pharmacogenomic variants was fea-sible using whole-exome sequencing. Actionable pharmacogenetic variants are common and relevant to patients undergoing cancer treatment. Universal pharmacogenomic screening can be per-formed using whole-exome sequencing data originally obtained for quality control purposes and could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and mercaptopurine.

Original languageEnglish
Article number4524
Issue number18
StatePublished - Sep 2021

Bibliographical note

Funding Information:
Funding: This research was funded by the Markey Cancer Research Informatics Shared Resource Facility National Cancer Institute Cancer Center Support Grant, grant number P30 CA177558.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • 5-fluorouracil
  • Cancer
  • Irinotecan
  • Mercaptopurine
  • Pharmacogenomics
  • Real word

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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