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Evaluation of the Role of the KRAS Gene Polymorphism LCS6 (rs61764370) in Iraqi Women with Ovarian Cancer.

ABSTRACT: In carcinogenesis, KRAS is an essential oncogene that plays a key function. The polymorphism of rs61764370 is a candidate for cancer susceptibility in KRAS3' untranslated region. The current study aimed to determine the role and impact of the KRAS gene polymorphism (rs61764370 T>G) on the risk of ovarian cancer development in the Iraqi population. In total, 84 ovarian cancer patients and 28 ovarian benign tumors were involved in a case-control study. DNA extraction from the formalin-fixed/paraffin-embedded tissues, followed by the sequencing of PCR products was carried out in genetic analysis for the detection of the KRAS polymorphism (rs61764370 T>G). The results showed that the frequencies of the KRAS gene polymorphism (rs61764370) in ovarian cancer patients were 78 (92.85%) and 6 (7.15%) with genotypes homozygote TT and heterozygote TG, respectively. These corresponding values in patients with benign ovarian tumors were 25 (89.3%) and 3 (10.7%) with homozygote TT and heterozygote TG, respectively. None of the patients either with malignant or benign tumors have been detected with homozygote genotype GG. Genotype frequency of the TT and TG showed that the heterozygote TT genotype vs. TG and T allele vs. G allele were more frequent in malignant and benign tumors (P≤0.01). Statistically, there was no association between the KRAS polymorphism and the clinical characteristics of ovarian cancer patients, such as age, family history, menopause, histological type, tumor size, or tumor stage. In conclusion, a significant association was found between rs61764370 and the risk of ovarian cancer in the Iraqi population, particularly those with genotypes homozygote TT. On the other hand, genotypes had no relationship with any of the clinical characteristics of ovarian cancer patients. Additional well-designed studies with larger sample sizes are recommended to validate the precise role of KRAS LCS6 variations in ovarian cancer risk.

SUBMITTER: Ghazi Jumaa M

PROVIDER: S-EPMC9288620 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cancer is a genetic disease that is highly influenced by environmental factors. To determine the risk factors of squamous cell carcinoma of the head and neck, two polymorphisms, solute carrier family 23 member 2 (SLC23A2-05 [rs4987219]) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-LCS6 (rs61764370), and environmental factors, including smoking and alcohol consumption, were studied in a population. The present study included 165 males diagnosed with squamous cell carcinoma of the head and neck. The control group consisted of 230 healthy male subjects without cancer or a family history of cancer. The SLC23A2-05 and KRAS-LCS6 polymorphisms were analyzed by polymerase chain reaction followed by enzymatic digestion. All patients and healthy subjects were assessed with regard to their smoking habit and alcohol consumption as these are considered to be risk factors for cancer. The statistical analysis was performed using logistic regression, Fisher's exact and ?2 tests. Additional analyses were performed using the programs, multi-factor dimensionality reduction (MDR; version 2.0) and MDR permutation test (version 0.4.7), which consider all variables as risk factors simultaneously. The results of the present study demonstrate that the SLC23A2-05 and KRAS-LCS6 polymorphisms are not a risk factor for squamous cell carcinoma of the head and neck. In the same samples, the association of alcohol consumption (P<0.001) and smoking habit (P<0.001) with cancer presence was positive when each variable was considered individually. Concerning the environmental factors, a positive association of smoking habit and alcohol consumption with cancer, although not with ethnicity (ratio, 1.0244; testing balance accuracy, 0.8733; P<0.001) was identified using the MDR tool, which analyzed the variables and polymorphism genotypes simultaneously. In conclusion, in the present study, squamous cell carcinoma of the head and neck was highly affected by environmental factors when compared with the affect of SLC23A2-05 and KRAS-LCS6 polymorphisms.

Project description:BACKGROUND:Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. PATIENTS AND METHODS:We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. RESULTS:A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). CONCLUSION:This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.

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Evaluation of the Role of the KRAS Gene Polymorphism LCS6 (rs61764370) in Iraqi Women with Ovarian Cancer.

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