الفهرس 
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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.