Concordance of Pharmacogenetic Markers in Germline and Colorectal Tumor DNA

Abstract

Introduction: Most cancer pharmacogenetic studies use germline DNA, as tumor tissue is often inaccessible in the advanced disease setting. However, this relies on the assumption that germline DNA is representative of the tumor genotype. To date, there has been little attention paid to defining the relationship between tumor and germline genomes. Materials and methods: This study compared 28 polymorphisms in 13 genes of high importance to cancer pharmacogenetics from ten different chromosome regions, in DNA from normal mucosa and colon tumors in 44 paired samples. Results: 93% of samples had one or fewer genotype discrepancies. 77% of patients had intraindividual genotypes in complete concordance. In addition, although microsatellite instability (MSI) was identified in 20% of tumors, no significant association between MSI and genotype discrepancies was observed (p = 0.672). Conclusions: While this data validates the use of germline DNA pharmacogenetics in colorectal cancer, statistical analysis and modeling of pharmacogenetic data should be employed to incorporate this small, but important, source of error.

Keywords::

• genotype
• germline
• microsatellite instability
• pharmacogenetics
• tumor

Acknowledgments

The authors wish to thank Christi Ralph, Cristi King, Ranjeet Ahluwalia, Chris Rose and Jinsheng Yu for technical assistance with this project. The authors also thank the Alvin J Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St Louis, Missouri, for the use of the Tissue Procurement Core, which provided the clinical samples for this study. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. SM and HLM are supported by R21 CA102461 and the NIH Pharmacogenetics Research Network (U01 GM63340) [101].

Additional information

Funding

The authors wish to thank Christi Ralph, Cristi King, Ranjeet Ahluwalia, Chris Rose and Jinsheng Yu for technical assistance with this project. The authors also thank the Alvin J Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St Louis, Missouri, for the use of the Tissue Procurement Core, which provided the clinical samples for this study. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA91842. SM and HLM are supported by R21 CA102461 and the NIH Pharmacogenetics Research Network (U01 GM63340)