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Worldwide, over 1 million cases of colorectal cancer (CRC) were reported in 2002, with a 50% mortality rate, making CRC the second most common cancer in adults. Certain racial/ethnic populations continue to experience a disproportionate burden of CRC. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been associated with a lower risk of CRC. The authors performed both a meta-analysis (29 studies; 11,936 cases, 18,714 controls) and a pooled analysis (14 studies; 5,068 cases, 7,876 controls) of the C677T MTHFR polymorphism and CRC, with stratification by racial/ethnic population and behavioral risk factors. There were few studies on different racial/ethnic populations. The overall meta-analysis odds ratio for CRC for persons with the TT genotype was 0.83 (95% confidence interval (CI): 0.77, 0.90). An inverse association was observed in whites (odds ratio = 0.83, 95% CI: 0.74, 0.94) and Asians (odds ratio = 0.80, 95% CI: 0.67, 0.96) but not in Latinos or blacks. Similar results were observed for Asians, Latinos, and blacks in the pooled analysis. The inverse association between the MTHFR 677TT polymorphism and CRC was not significantly modified by smoking status or body mass index; however, it was present in regular alcohol users only. The MTHFR 677TT polymorphism seems to be associated with a reduced risk of CRC, but this may not hold true for all populations.

The present study aimed to prospectively investigate the influence of thymidylate synthase (TS) polymorphisms (5'-TSER, 3'-TSUTR) on the disease-free survival (DFS) and overall survival (OS) of patients with colorectal cancer (CRC) who were treated with adjuvant 5-fluorouracil (5-FU) therapy. Patients were followed up for 19+/-14 months (median+/-SD). TS genotypes were determined from the peripheral blood mononuclear cells of 166 patients by polymerase chain reaction-polyacrylamide gel electrophoresis and restriction fragment length polymorphism methods. 5'-TSER 3R homozygotes showed significantly longer DFS (P = 0.048) and OS (P = 0.009). The 5'-TSER and 3'-TSUTR genotype combination groups showed a significant difference for DFS (P = 0.039) and OS (P = 0.029). Significantly better DFS (P = 0.049) and OS (P = 0.043) were observed for 6 bp/6 bp genotypes in 5'-TSER heterozygotes (n = 80). Based on this, and on hazard ratios obtained by Cox regression analysis of the DFS of genotype-combinations, the patients were classified as belonging to prognostic groups A and B. The DFS and OS of these two groups showed a highly significant difference (P = 0.002 and 0.001). In the multivariate Cox regression model, beside tumour location, the prognostic classification (groups A and B) proved to be an independent prognostic factor. Our data suggest that those TS genotypes and their combinations (group A: 3R/3R with any 3'-TSUTR genotype and 2R/3R with 6 bp/6 bp), which have been reported earlier as having high TS expression, predict significantly longer DFS and OS. We found that a combination of germline TS polymorphisms is an independent prognostic marker in selecting CRC patients with worse prognosis, and it may be worthwhile to examine whether these patients would benefit from an alternative therapy.

Background:Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or metastatic ACC, respectively, was evaluated.Methods:Eligible patients (9 with locally advanced tumour and 12 with metastases) had positive tumour EGFR expression. The cetuximab loading dose (400 mg m−2) was followed by 250 mg m−2 per week. Locally advanced tumours were irradiated (mean dose 65 Gy) and treated with concomitant cisplatin (75 mg m−2, intravenously). Patients with metastases received concomitant cisplatin and 5-fluorouracil (4 × 1000 mg m−2).Results:For patients with locally advanced disease (median follow-up: 52 months), the median progression-free survival (PFS) was 64 months and the 2-year overall survival (OS) rate was 100%. For patients with metastases (median follow-up: 72 months), the median PFS and OS were 13 and 24 months, respectively. In both groups the objective response rate was >40%. Skin rash, in-field dermatitis, mucositis and vomiting were the most frequent grade 3/4 adverse events.Conclusion:In this single-arm study, the efficacy of cetuximab plus chemoradio- or chemotherapy appeared favourable as compared with historical controls. All side effects were manageable and did not hamper the treatment.

Background: Epidemiological studies suggested the chemopreventive role of higher calcium intake in colorectal carcinogenesis. We examined genetic polymorphisms that might influence calcium metabolism: lactase (LCT) gene 13910 C/T polymorphism causing lactose intolerance and calcium-sensing receptor (CaSR) gene A986S polymorphism as a responsible factor for the altered cellular calcium sensation.

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BackgroundAssociation between rectal or colon cancer risk and serine hydroxymethyltransferase 1 (SHMT1) C1420T or methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker of folate metabolism was also investigated.MethodsThe SHMT1 and MTHFR genotypes were determined by real-time PCR and PCR-RFLP, respectively in 476 patients with rectal, 479 patients with colon cancer and in 461 and 478, respective controls matched for age and sex. Homocysteine levels were determined by HPLC kit. The association between polymorphisms and cancer risk was evaluated by logistic regression analysis adjusted for age, sex and body mass index. The population stratification bias was also estimated.ResultsThere was no association of genotypes or diplotypes with colon cancer. The rectal cancer risk was significantly lower for SHMT1 TT (OR = 0.57, 95% confidence interval (CI) 0.36-0.89) and higher for MTHFR CT genotypes (OR = 1.4, 95%CI 1.06-1.84). A gene-dosage effect was observed for SHMT1 with progressively decreasing risk with increasing number of T allele (p = 0.014). The stratified analysis according to age and sex revealed that the association is mainly present in the younger (< 60 years) or male subgroup. As expected from genotype analysis, the SHMT1 T allele/MTHFR CC diplotype was associated with reduced rectal cancer risk (OR 0.56, 95%CI 0.42-0.77 vs all other diplotypes together). The above results are unlikely to suffer from population stratification bias. In controls HCY was influenced by SHMT1 polymorphism, while in patients it was affected only by Dukes' stage. In patients with Dukes' stage C or D HCY can be considered as a tumor marker only in case of SHMT1 1420CC genotypes.ConclusionsA protective effect of SHMT1 1420T allele or SHMT1 1420 T allele/MTHFR 677 CC diplotype against rectal but not colon cancer risk was demonstrated. The presence of SHMT1 1420 T allele significantly increases the HCY levels in controls but not in patients. Homocysteine could be considered as a tumor marker in SHMT1 1420 wild-type (CC) CRC patients in Dukes' stage C and D. Further studies need to clarify why SHMT1 and MTHFR polymorphisms are associated only with rectal and not colon cancer risk.

Low-expression alleles in thymidylate synthase (TYMS) were associated with decreased DFS and overall survival (DFS:hazard ratio [HR] exploration 2.65 [1.40-4.65]; p = 0.004, HR validation 1.69 [1.03-2.66]; p = 0.03). A specific multifactor dimensionality reduction derived combination of dihydropyrimidine dehydrogenase and TYMS polymorphisms was associated with increased DFS (HR exploration 0.69 [0.49-0.98]; p = 0.04, HR validation 0.66 [0.45-0.95]; p = 0.03). Specific combinations of functional polymorphisms in DPYD and TYMS were demonstrated to be associated with DFS and overall survival in patients receiving adjuvant 5-FU-based treatment. Specifically high TYMS expression alleles seem to be associated with decreased DFS.