SMAD4 - Molecular gladiator of the TGF-β signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRAS proto-oncogene

<p>Abstract</p> <p>Background</p> <p>The development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the <it>SMAD4 </it>gene mutations with <it>KRAS </it>mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of <it>SMAD4 </it>gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and <it>KRAS </it>mutant genotype.</p> <p>Methods</p> <p>We examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of <it>SMAD4 </it>and exon 1 of <it>KRAS </it>by PCR-SSCP and/or PCR-Direct sequencing.</p> <p>Results</p> <p>The overall mutation rate of mutation cluster region (MCR) region of <it>SMAD4 </it>gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the <it>SMAD4 </it>gene mutants were found to have mutations in <it>KRAS </it>gene as well. The association between the <it>KRAS </it>mutant genotype with <it>SMAD4 </it>mutants was found to be significant (P =< 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the <it>SMAD4 </it>gene (P =< 0.05).</p> <p>Conclusion</p> <p>Our study suggests that <it>SMAD4 </it>gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the <it>KRAS </it>mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.</p

Role of TLR4 gene polymorphisms in the colorectal cancer risk modulation in ethnic Kashmiri population – A case–control study

AbstractBackgroundColorectal carcinogenesis has been found to be associated with the polymorphic status of Toll-like receptor 4 gene in various populations of the world.AimThe aim of the study was to determine the genetic association of TLR4 gene polymorphisms (Asp299Gly and Thr399Ile) with disease susceptibility and risk development in colorectal cancer (CRC) patients of Kashmir, India.Materials and methodsGenotype frequencies of TLR4 polymorphisms (Asp299Gly and Thr399Ile) were compared between 120 CRC patients and 200 healthy controls using PCR-RFLP method.ResultsWe did not find any significant association between the TLR4 gene polymorphisms and the CRC cases (p>0.05). However CT genotype (Thr399Ile) showed modest elevated risk of the development of CRC [OR=1.78 95% CI (0.88–3.5)]. Also G allele (AG genotype) of TLR-4 Asp299Gly polymorphism was found to be significantly associated with the male gender (p value=0.006) and involvement of Nodes (p value=0.01) whereas, T allele (CT genotype) of Thr399Ile polymorphism showed significant association with the smoking status (p value=0.03).ConclusionOur results suggest that TLR4 gene polymorphism is not a key modulator of the risk of developing colorectal cancer in Kashmiri population

Analysis of molecular aberrations of Wnt pathway gladiators in colorectal cancer in the Kashmiri population

<p>Abstract</p> <p>The development and progression of colorectal cancer (CRC) is a multi-step process, and the Wnt pathways with its two molecular gladiators adenomatous polyposis coli (<it>APC</it>) and <it>β-catenin </it>plays an important role in transforming a normal tissue into a malignant one. In this study, we aimed to investigate the role of aberrations in the <it>APC </it>and <it>β-catenin </it>genes in the pathogenesis of CRC in the Kashmir valley, and to correlate it with various clinicopathological variables. We examined the paired tumour and normal-tissue specimens of 86 CRC patients for the occurrence of aberrations in the mutation cluster region (MCR) of the <it>APC </it>gene and exon 3 of the β-<it>catenin </it>gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and/or PCR-direct sequencing. Analysis of promoter hypermethylation of the <it>APC </it>gene was also carried out using methylation-specific PCR (MS-PCR). The overall mutation rate of the MCR of the APC gene among 86 CRC cases was 12.8 per cent (11 of 86). Promoter hypermethylation of <it>APC </it>was observed in 54.65 per cent (47 of 86) of cases. Furthermore, we found a significant association between tumour location, tumour grade and node status and the methylation status of the <it>APC </it>gene (<it>p </it>≤ 0.05). Although the number of mutations in the <it>APC </it>and <it>β-catenin </it>genes in our CRC cases was very low, the study confirms the role of epigenetic gene silencing of the pivotal molecular gladiator, <it>APC</it>, of the Wnt pathway in the development of CRC in the Kashmiri population.</p

Squamous cell carcinoma of rectum presenting in a man: a case report

Abstract Background Primary squamous cell carcinomas of the colorectum are very uncommon. Until now, to the best of our knowledge, only 114 cases of squamous cell carcinoma in the colorectum exist in the reported literature. Here we report a case of squamous cell carcinoma of the rectum in the ethnic Kashmiri population in northern India. Case Presentation The case of a 60-year-old male patient (Asian) with a pure squamous cell carcinoma of the rectum is presented here. The patient underwent a curative surgery with concomitant chemotherapy. Two years after the initial curative resection of the tumor he is still alive. Conclusion The prognosis for squamous cell carcinoma of the colorectum is worse than for that of adenocarcinoma, because of the delayed diagnosis. The etiopathogenicity of squamous cell carcinoma of the colorectum is discussed. Surgical resection of the lesion seems to be the treatment of choice. Chemotherapy also helps in improvement of the prognosis.</p

Strong association of interleukin-6 −174G/C promoter single nucleotide polymorphism with a decreased risk of colorectal cancer in ethnic Kashmiri population: A case control study

Chronic inflammation increases the risk of development of various cancers, including colorectal cancer. Interleukin-6 has been described as a key regulator of colorectal cancer development and is important in the process of colorectal tumorigenesis largely through the regulation of tumor-promoting inflammation. Several studies have reported the association of various polymorphisms in human interleukin-6 gene including IL-6 −174G/C single nucleotide polymorphism with various cancers, including colorectal cancer, but the results are mixed and inconclusive. The aim of this study was to analyze the association of IL-6 −174G/C promoter single nucleotide polymorphism with colorectal cancer risk and also to evaluate the modifying effects of possible IL-6 −174G/C single nucleotide polymorphism genotypes on different risk factors of colorectal cancer or the reciprocal effect in ethnic Kashmiri population through a case control setup. The genotype frequencies of IL-6 −174G/C promoter single nucleotide polymorphism were compared between 142 colorectal cancer patients and 184 individually matched healthy controls by using polymerase chain reaction–restriction fragment length polymorphism method. The association between the IL-6 −174G/C single nucleotide polymorphism and colorectal cancer risk was examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. The possible effect measure modification of the association between the relevant single nucleotide polymorphism genotypes and colorectal cancer risk by various colorectal cancer risk factors including age, gender, and smoking status was also evaluated. Furthermore, the associations between these single nucleotide polymorphisms and various clinicopathological parameters, demographic variables, and environmental factors within the case group subjects with regard to colorectal cancer risk were also analyzed. The overall association between the IL-6 −174G/C single nucleotide polymorphism and the modulation of colorectal cancer risk was found to be highly significant (p = 0.001). The variant genotype (CC) was significantly associated with a decreased risk of colorectal cancer (odds ratio, 0.15 (95% confidence interval, 0.04–0.54); p = 0.004). Furthermore, the less common IL-6-174C allele was associated with a decreased risk of colorectal cancer (odds ratio, 0.49 (95% confidence interval, 0.33–0.73); p = 0.0006). The combined variant genotype (GC + CC) was also significantly associated with a decreased risk of colorectal cancer (odds ratio, 0.54 (95% confidence interval, 0.33–0.89); p = 0.015). This study demonstrates that there is a strong and highly significant association between the IL-6 −174G/C promoter single nucleotide polymorphism and a decreased risk of colorectal cancer in ethnic Kashmiri population. However, in order to substantiate our findings, this study needs to be replicated with larger sample size and with other ethnically defined populations with comparable colorectal cancer incidence. </jats:p