PubMed:19082493 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/19082493","sourcedb":"PubMed","sourceid":"19082493","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/19082493","text":"Combination of polymorphisms within 5' and 3' untranslated regions of thymidylate synthase gene modulates survival in 5 fluorouracil-treated colorectal cancer patients.\nIn the present study we explored the effect of three polymorphisms of the TS gene on overall and progression- free survival of colorectal cancer (CRC) patients subjected to 5FU chemotherapy. A 28 bp variable number of tandem repeats (VNTR), a G/C single nucleotide polymorphism (SNP), and a deletion of 6 bp at position 1494 were studied. The possible combined effect of these DNA polymorphisms on the clinical outcome of patients was also evaluated. A retrospective study was carried out on paraffin-embedded sections from 113 patients diagnosed of advanced CRC. TS genotyping methods were polymerase chain reaction (PCR) for VNTR and PCR, followed by restriction length fragment polymorphism (PCR-RFLP) for SNP and ins/del 6 bp. To study the combined effect of TS polymorphisms, four categories were defined accordingly to the level of expression attributed to SNP and ins/del 6 bp genotypes: C\u0026allele 6-, C\u00266+/6+, G\u0026allele6- and G\u00266+/6+. VNTR and ins/del 6 bp genotypes varied with tumour anatomical site: 2R/2R genotype was rare in left-sided tumours (7.0% vs. 26.3% of right-sided and 24.1% of rectal cancers; P\u003c0.01), where the variant allele 6- was very frequent (69.0%). Instead, most patients with right-sided tumours were wild-type homozygous 6+/6+ (63.9%) (P\u003c0.01). Heterozygous 6+/6- genotype was more frequent among tumours classified as C (50.0%) and D (76.5%) Dukes stages (P=0.05). None of the studied polymorphisms alone affected overall or progression-free survival (PFS). C\u00266+/6+ and G\u00266+/6+ combined genotypes were respectively associated to the best and worst PFS (P=0.03 when compared with each other), while combinations carrying the allele 6- determined an intermediate evolution that might be indicative of a variable response to chemotherapy. The rate of Dukes B stage tumours was unexpectedly high (59.1%) among patients with the unfavourable G\u00266+/6+ combination. In our study the combination of high TS expression genotypes G\u00266+/6+ identifies a group of high risk within CRC patients treated with 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