Pathological implications of Cx43 down-regulation in human colon cancer.

Connexin 43 is an important gap junction protein in vertebrates and is known for its tumor suppressive properties. Cx43 is abundantly expressed in the human intestinal epithelial cells and muscularis mucosae. To explore the role of Cx43 in the genesis of human colon cancer, we performed the expression analysis of Cx43 in 80 cases of histopathologically confirmed and clinically diagnosed human colon cancer samples and adjacent control tissue and assessed correlations with clinicopathological variables. Western blotting using anti-Cx43 antibody indicated that the expression of Cx43 was significantly down regulated (75%) in the cancer samples as compared to the adjacent control samples. Moreover, immunohistochemical analysis of the tissue samples confirmed the down regulation of the Cx43 in the intestinal epithelial cells. Cx43 down regulation showed significant association (p<0.05) with the histological type and tumor invasion properties of the cancer. Our data demonstrated that loss of Cx43 may be an important event in colon carcinogenesis and tumor progression, providing significant insights about the tumor suppressive properties of the Cx43 and its potential as a diagnostic marker for colon cancer.

Splice site and Germline variations of the MGMT gene in Esophageal cancer from Kashmir Valley: India.

OBJECTIVES: The aim of our investigation was to detect mutation or genetic polymorphisms in MGMT gene of esophageal cancer patients from Kashmir Valley (India). METHODOLOGY: The genetic polymorphisms or mutations in the coding exons 2, 3, 4 and 5 of MGMT gene were searched for in DNA samples from the frozen tumor tissues of 30 esophageal cancer patients from Kashmir. The PCR products were sequenced with fluorescently labelled terminators and separated on automatic sequencer. We developed a new PCR based RFLP approach for genotyping c.459A>G (p.Gly153Gly) variation in 71 esophageal cancer patients and 60 healthy controls. RESULTS: Two somatic variations c.274 +4G>A and c.274 + 22G>A were identified in Exon3-intron 4 boundary. A novel germline variation c.459A>G (p.Gly153Gly) was found in the exon 5 of an esophageal cancer patient. This germline variation was not found in any of the studied esophageal cancer patients and healthy controls except the patient where it has been found by direct sequencing. CONCLUSION: We identified novel sequence variants of the MGMT gene in esophageal cancer patients from Kashmir valley-India.

CYP1A1 polymorphisms and risk of lung cancer in the ethnic Kashmiri population.

The CYP1A1 category of enzymes plays a central role in the metabolic activation of major tobacco carcinogens. Several polymorphisms within the CYP1A1 locus have been identified and have been shown to be associated with lung cancer risk, particularly in Asian populations. Here we focused on the influence of three polymorphisms on lung cancer in ethnic Kashmiris, genotyping 109 lung cancer cases and 163 healthy controls by PCR-RFLP methods. While no polymorphic alleles in CYP1A1m4 (exon 7 thr to asn) site were detected in our population, the allele frequency of CYP1A1m1 (Msp1) and CYP1A1m2 (exon 7 ile to val) were 30.1 and 26.6 in controls and 44.5 and 38.9 in cases. The CYP1A1m1 and CYP1A1m2 variants were significantly associated with lung cancer susceptibility (ORs; 2.65, CI 95% = 1.562-4.49 and 2.24,CI 95%= 1.35-3.73).This risk was prominent in case of SCC compared with AC or other types of lung cancer. Stratified analysis showed a multiplicative interaction between tobacco smoking and variant CYP1A1m1 genotype on the risk of SCC. The ORs of SCC for non-smokers were 2.08 and 3.15 for smokers. When stratified by pack years, effect was stronger in the heaviest smokers (ORs= 6.00,95% CI= 1.672-21.532).The interaction between tobacco smoking and variant CYP1A1m2 genotype followed similar pattern. Our findings thus support the conclusion that CYP1A1m1 and m2 polymorphisms are associated with the smoking related lung cancer risk in Kashmiri population.