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Abstract Colorectal cancer is one of the most frequently diagnosed cancers in humans and a leading cause of death worldwide. Lifestyle-related factors as dietary habits, age, body weight, heavy alcohol consumption and smoking in addition to other factors as a positive family history, diabetes, chronic intestinal inflammation are associated with an increased risk for CRC. Genetic variability among CRC patients plays a key role for the differences in the response to adjuvant chemotherapy across populations. Single nucleotide polymorphisms of ERCC1 C118T and MTHFR C677T are considered molecular markers that may predict the response to chemotherapy with oxaliplatin such as FOLFOX regimen within metastatic CRC patients. The aim of the current study was to assess the effect of MTHFR C677T and ERCC1 C118T genes polymorphisms as possible risk factors for colorectal cancer susceptibility and to evaluate their effect on the response to FOLFOX chemotherapy in metastatic colorectal cancer patients. The study included 74 patients with metastatic colorectal cancer from those attending the oncology clinic - Medical Research Institute and from the outpatient oncology clinic - Faculty of Medicine -Alexandria University. The study also included 100 healthy volunteers as control group All patients were subjected to: 1. Full history taking including: personal data, medical history, family history, smoking and environmental risk factors for CRC. 2. Imaging using multislice CT chest and abdomen after 3 cycles and 6 cycles. 3. Tumor markers CEA, CA19.9 and complete laboratory work including: liver functions tests, kidney functions tests and complete blood count. 4. Molecular genetics testing for ERCC1 C118T and MTHFR C677T using PCRRFLP for the patients and the controls. All patients in this study were treated with three to six cycles of FOLFOX4 chemotherapy and their response to treatment was evaluated according to the Response Evaluation Criteria In Solid Tumors (RECIST). The results of the present study were as follows: i. The ages of the studied patients ranged from 19 to 70 years the mean ± standard deviation of 50.7 ± 12 years. ii. Females represented 54.1% while males represented 45.9%. Female to male ratio was 1:1.18. iii. Eleven patients (14.9%) were smokers while 63 patients (85.1%) were non smokers. In the control group 24% were smokers and 76% were non smokers. There was no statistical significant difference between smokers and non smokers among patients and control (P=0.137). iv. Forty three patients were overweight and obese (BMI ≥ 25kg/m2) including the 29 females and 14 males. A statistical significant association was observed between gender and body mass index in patient (p=0.006). v. A positive family history for CRC was reported in 6.75%. vi. The C/C genotype of the ERCC C118T locus polymorphisms was observed in twenty two (29.7%) patients compared with fifty four (54%) control, C/T genotype was shown in forty four (59.5%) patients compared with thirty eight (38%) control whereas the TT genotype was found in eight (10.8%) patients compared with eight (8 %) control. There was a statistical significant difference between distribution of ERCC C118T genotypes among case and control (P=0.006). vii. The C/C genotype of the MTHFR C677T locus polymorphisms was observed in thirty eight (51.4%) patients compared with forty one (41%) control while C/T genotype was shown in twenty seven (36.5%) patients compared with forty nine (49%) control while the T/T genotype was found in nine (12.2%) patients compared with ten (10 %) control. There was no statistical significant difference between distribution of MTHFR C677T genotype among patients and controls (P=0.257). viii. After treatment with FOLFOX chemotherapy, thirty six (48.6%) were responders (Complete Response and Partial Response) and thirty eight (51.4%) were non responders (Stable Disease and Progressive Disease). ix. The C/C genotype of the ERCC1 C118T locus polymorphisms was observed in eleven (30.6%) patients within responder group to FOLFOX chemotherapy compared with eleven (28.9%) within non responder, C/T genotype was shown in twenty two (61.1%) patients within responder compared with twenty two (57.9%) within non responder while the T/T genotype was found in three (8.3%) patients within responder compared five (13.2%) within non responder group. The difference was statistically insignificant (MCP=0.89). However the frequency of T/T genotype in the non responder group was higher compared to the responder, were all non responder having a T/T genotype suffered progressive disease. x. The C/C genotype of the MTHFR C677T locus polymorphisms was observed in seventeen (47.2%) patients within responder group to FOLFOX chemotherapy compared with twenty one (55.3%) within non responder, C/T genotype was shown in seventeen (47.2%) patients within responder compared with ten (26.3%) within non responder while the T/T genotype was found in two (5.2%) patients within responder compared seven (18.4%) within non responder group. The difference was statistically insignificant (MCP =0.075). However the T/T genotype in the non responder group was observed more frequently than in the responder group. xi. FOLFOX induced hematological toxicity grade III (anemia and neutropenia) was reported in two (2.7%) patients in the currents study while diarrhea was observed in one (1.4%) patients. Neurotoxicity on the other hand was observed in five (6.8%) of patients. We did not observe a statistical significant association between ERCC1 C118T and MTHFR C677T genotypes and hematological, gastrointestinal (diarrhoea) or neurotoxicity on treatment with FOLFOX chemotherapy. |