title: Pathway based analysis of SNPs with relevance to 5-FU therapy: relation to intratumoral mRNA expression and survival.
abstract: Genetic factors are thought to play a role in resistance towards chemotherapeutic agents such as 5-fluorouracil (5-FU). Approximately 30 genes are directly or indirectly involved in 5-FU metabolism, and genetic variation in any of these may contribute to anti-tumor response. Polymorphisms in these genes were analyzed in relation to tumoral mRNA levels of 5-FU metabolizing genes, response to chemotherapy and survival. A total of 21 genetic variants were studied in 35 breast cancer patients treated with 5-FluoroUracil, mitomycin (FUMI) and in a similar cohort of 90 doxorubicin treated breast cancer patients. Genotype distributions were compared using 109 healthy controls. No significant association was found between any polymorphisms and response to chemotherapy as measured by shrinkage of tumor. However, carriers of 3 copies of the TYMS 5'UTR repeat had shorter survival than noncarriers (p = .048) in the FUMI treatment group, but not in the doxorubicin treated group. Carriers of 3 copies of the repeat were also more frequently observed in both patients groups than in healthy controls (p = .034). Several highly significant associations were observed between genotypes and expression levels of 5-FU metabolizing genes. A SNP in codon 72 of TP53 was revealed to be a key regulator of 5-FU metabolizing genes such as DHFR and MTHFR, constituting 50% of all significant associations observed after FUMI therapy. These data suggest that 3 copies of the TYMS 5'UTR repeat may give a treatment specific reduced survival in breast cancer patients, and that TP53 may have a direct, allele specific, role in 5-FU mediated response.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Montebello, Oslo, Norway.
authors.forename: Silje H
authors.initials: SH
authors.lastname: Nordgard
authors.forename: Grethe I G
authors.initials: GI
authors.lastname: Alnaes
authors.forename: Björn
authors.initials: B
authors.lastname: Hihn
authors.forename: Ole Christian
authors.initials: OC
authors.lastname: Lingjaerde
authors.forename: Knut
authors.initials: K
authors.lastname: Liestøl
authors.forename: Anya
authors.initials: A
authors.lastname: Tsalenko
authors.forename: Therese
authors.initials: T
authors.lastname: Sørlie
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000378:metabolism / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016022:Case-Control Studies; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016685:Mitomycin; D004317:Doxorubicin; D005472:Fluorouracil