TS genotyping

The TS gene is localized to the short arm of chromosome 18 at chromosome band 18p 11.32 (64). Chromosome 18 is generally known to be a site of frequent deletions in colorectal cancer tissues (64). Therefore it is highly probably that allelic imbalance occurs at the TS locus in some colorectal tumors. Zinzindohoue et al. were the first to report on the idea of LOH at the TS locus. The authors showed that the TS genotype from 2R/3R heterozygotes differed in ratio between 2R and the 3R bands. The observed LOH frequency at the TS locus was 63% (31 of 50) (65). 

TS genotypes and their combinations, which have been reported earlier with high TS expression, show longer OS/PFS (3R/3R with ary 3 -UTR genotype and 2R/3R with +6bp/+6bp)... 

Patients with TS low expression genotype (A-gronp), had an overall better RR, DFS and OS than the TS high expression genotype TS genotype as independent predictor ofRR,PFS, OS... 

Genotyping of the TS Promoter Variable Tandem Repeat and Clinical Outcome... 

Patients with 3R/-6bp haplotype, which represented 22.8% of the study population analyzed, showed a benefit (p = 0.012) to adjuvant chemotherapy. The strength of this association was stronger for haplotypes harboring the TS 1494-6bp/-6bp allele, suggesting a prominent role of the 3 -UTR polymorphism. These results are in line with observations by Jakobsen et al. for patients in the metastatic setting (68). A different study by Hitre et al. verified better OS (p = 0.009) and PFS (p = 0.048) for patients receiving adjuvant 5-FU based chemotherapy with the 3R variant compared to other genotype combinations (69). 

The presence of at least one high TS expression genotype showed independent adverse prognostic role in mnltivariant analysis... 

The analysis of the predictive role of TS polymorphisms may be more complex if the 6-bp deletion/insertion (del/ins) polymorphism in the 3 UTR is added for consideration. The 6-bp deletion allele may cause mRNA instability and reduce intratumoral TS mRNA levels (32). The improved study design on the pharmacogenetic effect of TS polymorphisms should include a global evaluation of the combined VNTR, G/C, and 6-bp del/ins polymorphisms (33). The same global analysis applies to other genes, especially when the functional polymorphism is unclear. Haplotypes may be more informative than individual genotypes. Haplotype tag SNPs (htSNPs) based on the international HapMap project may represent the next wave of pharmacogenomic studies. 

A subsequent study on two patients with severe TS (TS2) revealed two de novo missense mutations in exon 8 of the dominant Cav 1.2 splice variant found in heart and brain (Splawski et al., 2005). All patients had a heterozygous genotype suggesting the mutations are dominant. 

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