Identification of novel germline polymorphisms governing capecitabine sensitivity

Authors

  • Peter H. O'Donnell MD,

    1. Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
    2. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois
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    • The first 2 authors contributed equally to this article.

  • Amy L. Stark PhD,

    1. Department of Human Genetics, The University of Chicago, Chicago, Illinois
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    • Fax: (773) 702-9268

  • Eric R. Gamazon MS,

    1. Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois
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  • Heather E. Wheeler PhD,

    1. Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
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  • Bridget E. McIlwee BA,

    1. Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
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  • Lidija Gorsic BS,

    1. Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
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  • Hae Kyung Im PhD,

    1. Department of Health Studies, The University of Chicago, Chicago, Illinois
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  • R. Stephanie Huang PhD,

    1. Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
    2. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois
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  • Nancy J. Cox PhD,

    1. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois
    2. Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois
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  • M. Eileen Dolan PhD

    Corresponding author
    1. Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois
    2. Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago, Chicago, Illinois
    • 900 East 57th Street, KCBD 7100, The University of Chicago, Chicago, IL 60637
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    • Fax: (773) 702-9268


Abstract

BACKGROUND:

Capecitabine, an oral 5-fluorouracil (5-FU) prodrug, is widely used in the treatment of breast, colorectal, and gastric cancers. To guide the selection of patients with potentially the greatest benefit of experiencing antitumor efficacy, or, alternatively, of developing toxicities, identifying genomic predictors of capecitabine sensitivity could permit its more informed use.

METHODS:

The objective of this study was to perform capecitabine sensitivity genome-wide association studies (GWAS) using 503 well genotyped human cell lines from individuals representing multiple different world populations. A meta-analysis that included all ethnic populations then enabled the identification of novel germline determinants (single nucleotide polymorphisms [SNPs]) of capecitabine susceptibility.

RESULTS:

First, an intrapopulation GWAS of Caucasian individuals identified reference SNP 4702484 (rs4702484) (within adenylate cyclase 2 [ADCY2]) at a level reaching genome-wide significance (P = 5.2 × 10−8). This SNP is located upstream of the 5 methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene, and it is known that the enzyme for MTRR is involved in the methionine-folate biosynthesis and metabolism pathway, which is the primary target of 5-FU-related compounds, although the authors were unable to identify a direct relation between rs4702484 and MTRR expression in a tested subset of cells. In the meta-analysis, 4 SNPs comprised the top hits, which, again, included rs4702484 and 3 additional SNPs (rs8101143, rs576523, and rs361433) that approached genome-wide significance (P values from 1.9 × 10−7 to 8.8 × 10−7). The meta-analysis also identified 1 missense variant (rs11722476; serine to asparagine) within switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin (SMARCAD1), a novel gene for association with capecitabine/5-FU susceptibility.

CONCLUSIONS:

Toward the goal of individualizing cancer chemotherapy, the current study identified novel SNPs and genes associated with capecitabine sensitivity that are potentially informative and testable in any patient regardless of ethnicity. Cancer 2011. © 2011 American Cancer Society.

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