1614P - Pharmacogenetic evaluation of targeted DNA sequencing in cancer patients

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Eric Seiser
Citation Annals of Oncology (2014) 25 (suppl_4): iv546-iv563. 10.1093/annonc/mdu358
Authors E. Seiser1, N. Gillis1, J. Parker2, D.N. Hayes2, D. Eberhard2, K. Richards2, J.T. Auman2, F. Innocenti1
  • 1Division Of Pharmacotherapy And Experimental Therapeutics, The University of North Carolina at Chapel Hill, 27599 - Chapel Hill/US
  • 2Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, 27599 - Chapel Hill/US

Abstract

Aim

Germline sequence variation and somatic alterations in genes associated with drug processing can determine therapeutic response in cancer patients, and next-generation sequencing (NGS) of these genes generates individualized pharmacogenetic data.

Methods

Targeted Illumina NGS of over 200 genes (including known druggable targets, cancer pathogenesis and drug response genes) was performed for matched germline and tumor DNA from patients representing many common cancer types. Aligned sequence data was used for genotype variant calling in both germline and tumor DNA and for mutation and copy number identification within tumors. Genetic ancestry was determined from germline genotypes. Somatic alterations within genes relevant to the pharmacology of anticancer agents were examined in breast and colorectal cancers, two frequent types in the study.

Results

The 208 patients sequenced were mainly Caucasian (78%) and African American (16%). The most common cancer types included gastrointestinal (19%), genitourinary (18%), and breast (13%). A total of 38 pharmacogenetic variants in 18 genes, including cytochrome P450 genes, were in Hardy-Weinberg equilibrium in Caucasian and African American populations. Observed genotype concordance of these variants in matched germline and tumor DNA was greater than 95% at all surveyed loci across all cancer types and greater than 90% at all loci in breast and colorectal cancers. Analysis of 16 genes associated with anticancer agents in breast and colorectal cancers identified somatic mutations in almost 50% of patients with these cancers, including predicted amino acid changes in ABCB1, DPYD, and CYP2C8. Aberrant tumor DNA copy numbers were sporadically observed in most of these genes, although recurrent deletions of DPYD and SULT1A1 were present in both tumor types.

Conclusions

NGS of pharmacogenes from an individual's non-malignant and tumor tissue provides a comprehensive catalog of germline variants and both known and novel somatic alterations. The integration of genetic data from germline and tumor may aid in elucidating the pharmacology underlying therapeutic effect. Ongoing analysis of the effect of these molecular alterations on drug response will be presented at the meeting.

Disclosure

All authors have declared no conflicts of interest.