title: Identification of novel germline polymorphisms governing capecitabine sensitivity.
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.
authors.affiliation: Section of Hematology-Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Peter H
authors.initials: PH
authors.lastname: O'Donnell
authors.forename: Amy L
authors.initials: AL
authors.lastname: Stark
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: Bridget E
authors.initials: BE
authors.lastname: McIlwee
authors.forename: Lidija
authors.initials: L
authors.lastname: Gorsic
authors.forename: Hae Kyung
authors.initials: HK
authors.lastname: Im
authors.forename: R Stephanie
authors.initials: RS
authors.lastname: Huang
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000069287:Capecitabine; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D044465:White People
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil