{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["O'Donnell PH"],"funding":["NCRR NIH HHS","NCI NIH HHS","NIGMS NIH HHS"],"pagination":["4063-73"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC3413892"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["118(16)"],"pubmed_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."],"journal":["Cancer"],"pubmed_title":["Identification of novel germline polymorphisms governing capecitabine sensitivity."],"pmcid":["PMC3413892"],"funding_grant_id":["P50 CA125183","K08 GM089941-01","K12 CA139160","UO1 GM61393","F32 CA136123","P50 CA125183-01","TL1 RR025001","TL1 RR025001-04","P50 CA125183-05","P50 CA125183-04","P50 CA125183-03","P50 CA125183-02","K08 GM089941","U01 GM061393","U01 GM061393-13","U01 GM061393-12","TL1 RR25001","F32 CA136123-01A1","U01 GM061393-11"],"pubmed_authors":["Stark AL","Dolan ME","Gamazon ER","O'Donnell PH","Huang RS","McIlwee BE","Cox NJ","Wheeler HE","Im HK","Gorsic L"],"additional_accession":[]},"is_claimable":false,"name":"Identification of novel germline polymorphisms governing capecitabine sensitivity.","description":"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.","dates":{"release":"2012-01-01T00:00:00Z","publication":"2012 Aug","modification":"2021-02-19T23:19:24Z","creation":"2019-03-27T00:56:27Z"},"accession":"S-EPMC3413892","cross_references":{"pubmed":["22864933"],"doi":["10.1002/cncr.26737"]}}