Integration of Germline Pharmacogenetics Into a Tumor Sequencing Program.


Evidence-based guidelines inform treatment decisions for patients for whom germline genetic information is available. Our real-time tumor sequencing program, which makes precision treatment decisions for patients with cancer, produces matched germline information, providing a unique opportunity to efficiently implement pharmacogenetics and benefit patients.

The germline genetic database from the Michigan Oncology Sequencing (MI-Oncoseq) program was searched for 21 clinically actionable polymorphisms in five cancer-relevant genes: <i>TPMT</i>, <i>DPYD</i>, <i>CYP2C19</i>, <i>CYP3A5</i>, and <i>UGT1A1</i>. Residual germ line DNA was sent to an external Clinical Laboratory Improvement Amendments-approved laboratory for confirmatory genotyping. The medical records of MI-Oncoseq patients with actionable phenotypes were searched for receipt of relevant drugs and to determine whether having genetic information at the time of treatment would have led to a treatment recommendation.

All nine variants in <i>TPMT</i>, <i>DPYD</i>, and <i>CYP2C19</i> that were detected in MI-Oncoseq were confirmed by external genotyping. Genotype determinations could not be made for <i>CYP3A5*3</i>, <i>UGT1A1*28</i>, or <i>UGT1A1*80</i>. On the basis of retrospective assessment of 115 adult and pediatric patient records, 4.3% (n = 5) had a potentially clinically actionable phenotype for <i>TPMT</i>, <i>DPYD</i>, or <i>CYP2C19</i> and received a relevant medication. After accounting for differences in adult and pediatric recommendations, three of these patients could have received a treatment recommendation at the time of prescribing.

Germline genotype determinations for <i>TPMT</i>, <i>DPYD</i>, and <i>CYP2C19</i> can be used to make evidence-based treatment recommendations in MI-Oncoseq patients. Although the proportion of patients for whom recommendations can be made is small, this added value to MI-Oncoseq and patient care comes at no additional genotyping cost. Pharmacogenetic assessment should be integrated into tumor sequencing programs that genotype matched germline DNA; however, the complexity and additional cost of implementing pharmacogenetics remain challenging.

  • Anderson B
  • Chinnaiyan A
  • Frank K
  • Glatz A
  • Hertz DL
  • Lonigro RJ
  • Mody RJ
  • Mora E
  • Pasternak AL
  • Rabban E
  • Robinson DR
  • Vats P
  • Wu YM
PubMed ID
Appears In
JCO Precis Oncol, 2018, 2