الفهرس 
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Abstract
Colorectal cancer is the third most common cancer in males and the second in females. CRC is also the fourth most frequent cause of cancer mortality worldwide. It is the most common malignancy of the gastrointestinal tract. Developing countries have unusually high proportion of early onset CRC. CRC is more frequent in males compared to females.
One of the important causes of cancer in human is the un-repaired damaged DNA. Human cells have several pathways in repairing damaged DNA. These pathways include Base Excision Repair (BER), Nucleotide Excision Repair (NER), Double-strand break repair and Mismatch Repair (MMR). These repair pathways are important for keeping the cells healthy. They recognize the damaged DNA and repair it. Un-repaired damage can result in un-regulated cell growth and carcinogenesis.
The XPD gene is a part of NER pathway, while XRCC-1 gene is a part of BER pathways. These genes play an important role in DNA repair. XPD Lys751Gln and XRCC-1 Arg399Gln polymorphisms alter the repair efficacy of these genes. These polymorphisms alter the risk of CRC and affect the CRC patient’s clinical response to FOLFOX chemotherapy.
FOLFOX chemotherapy is a third generation platinum derivative. It is composed of 5-fluorouracil with leucovorin and oxaliplatin. FOLFOX chemotherapy is widely used in treatment of CRC.
The aim of the current study was to evaluate the effect of XPD Lys751Gln and the XRCC-1 Arg399Gln polymorphisms on the susceptibility to colorectal cancer and the response to FOLFOX regimen in treated CRC patients.
To fulfill these objectives, the study was conducted on 67 colorectal cancer patients, with histopathologically confirmed colon adenocarcinoma, who were recommended to be treated with FOLFOX chemotherapy. The study also included 118 healthy volunteers as a control
group. Blood samples were obtained from both cases and control, DNA extraction and PCR-RFLP were then performed to assess the XPD Lys751Gln and XRCC-1 Arg399Gln polymorphisms in relation to response and toxicity of FOLFOX in treated CRC patients. All patients were also subjected to the following: history taking (personal data, smoking history, medical and family history), body mass index and evaluation of tumor characteristics (pathological analysis, lymph nodes examination, radiological investigation, tumor grade and stage).The volunteers in the control group were subjected to history taking and body mass index estimation. Both group were subjected to molecular analysis of the XPD Lys751Gln and XRCC-1 Arg399Gln polymorphisms.
The results ofthe present study were as follow:
• The age of the affected cases ranged from 23-70 years (mean 48.4, median 48), while the age of onset of CRC in affected patients was; below 50 years in 37 CRC patients (55.2%) and in (44.8%) of patients above or equal to 50 years.There was no significant association between XPD Lys751Gln or XRCC1 Arg399Gln polymorphisms and the age of onset in CRC patients.
• Obesity was observed in 34.3% of patients (13.4% males and 20.9% females). There was no statistical significant association between the obesity and the risk of CRC in affected patients.
• There were 16 smoker patients (24%) compared to 39 smokers in the control group (33%). No statistical significant association was foundbetween the smoking habits and the risk of CRC in affected patients.
• Diabetes mellitus type II was reported in only 6% of CRC patients. All of the diabetic patients were females.
• There were 56 patients (84%) with colon cancer while only 11 (16%) had rectal cancer.
• All the cases were metastatic CRC patients, where the number of metastatic sites ranged from one to more than one site. 88.1% of patients had single metastatic site mostly the liver (65% of patients).
• The XPD Lys751Gln polymorphism genotypes found were as follows (43.3% for the A/A genotype, 37.3% for the A/C genotype, 19.4% for the C/C genotype) among cases compared to (33.9% for the A/A genotype, 48.3% for the A/C genotype, 17.8% for the C/C genotype) among controls. There was no statistical significant association observed between the XPD Lys751Gln polymorphism and the risk of CRC.
• The XRCC-1 Arg399Gln polymorphism genotypes were as follows (23.9% for the G/G genotype, 68.7% for the G/A genotype, 7.5% for the A/A genotype) among cases compared to (15.3% for the G/G genotype, 73.7% for the G/A genotype, 11% for the A/A genotype) among controls. There was no statistical significant association observed between the XRCC1 Arg399Gln polymorphism and the risk of CRC.
• In the present study, there was no significant association between the XPD Lys751Gln polymorphism and clinical response to FOLFOX chemotherapy. The cases were distributed into responders (15% of the cases with A/A genotype, 18% with A/C and 12% with C/C) and the non-responders (28% of the cases with A/A genotype, 19.5% with A/C genotype and 7.5% with C/C genotype)
• There was also no significant association between the XRCC1 Arg399Gln polymorphism and clinical response to FOLFOX chemotherapy. The cases were distributed into responders (7.5% of the cases with G/G genotype, 31.5% with G/A and 6% with A/A) and the non-responders (16.5% of the cases with G/G genotype, 37% with G/A genotype and 1.5% with A/A genotype)
• There was no significant association between XPD Lys751Gln or XRCC1 Arg399Gln polymorphisms and theoccurance of oxaliplatin-related toxicities.