Arg399Gln polymorphism of XRCC1 gene and risk of colorectal cancer in Kashmir: A case control study.

The aim of this study was to investigate the role of the XRCC1 Arg399Gln polymorphism in the susceptibility of a Kashmiri population to colorectal cancer (CRC). We investigated the genotype distribution of the XRCC1 gene in 130 CRC cases in comparison with that of 150 healthy subjects. There was no direct significant association between the XRCC1 genotypes and CRC; however, the Arg/Gln genotype was associated with an elevated risk of CRC (OR>1.47) and the Gln/Gln variant genotype was associated with an increased risk of CRC in various clinicopathological parameters. This study suggests that the XRCC1 polymorphism is associated with an increased risk of CRC.

Gastric cancer in young patients.

AIM: The aim of this study was to see the clinical, pathological, and demographic profile of young patients with stomach carcinoma besides association with p53. PATIENTS AND METHODS: Prospective study of young patients with stomach carcinoma from January 2005 to December 2009. A total of 50 patients with age less than 40 years were studied. RESULTS: Male female ratio was 1 : 1.08 in young patients and 2.5 : 1 in older patients. A positive family history of stomach cancer in the first degree relatives was present in 10% of young patients. Resection was possible only in 50% young patients. 26% young patients underwent only palliative gastrojejunostomy. The most common operation was lower partial gastrectomy in 68%. Amongst the intraoperative findings peritoneal metastasis was seen in 17.4% in young patients. 50% young patients presented in stage IV as per AJCC classification (P value .004; sig.). None of the patients presented as stage 1 disease in young group. CONCLUSION: Early detection of stomach carcinoma is very important in all patients but in young patients it is of paramount importance.

The blues of P(16)INK(4a): aberrant promoter methylation and association with colorectal cancer in the Kashmir valley.

Hypermethylation of the promoter region of the p16INK4a (p16) gene plays a significant role in the development and progression of colorectal cancer (CRC). The aim of the present study was to establish the role of the methylation status of the p16 gene in 114 CRC cases and to correlate it with the various clinicopathological parameters. Analysis of p16 promoter methylation was performed by methylation-specific PCR. Forty-eight (42.1%) of the CRC cases were found to be methylated for the p16 gene in our population. The methylation status was found to be associated with the gender, lymph node status, tumour stage, smoking status and tumour grade of the CRC patients. p16 plays a pivotal role in tumour development and progression to advanced stages.

DNA repair gene 8-oxoguanine DNA glycosylase Ser326Cys polymorphism and colorectal cancer risk in a Kashmiri population.

8-Oxoguanine DNA glycosylase (OGG1) is one of the important base excision repair enzymes that repair 8-oxoguanine lesion incorporated within the DNA of an individual by reactive oxygen species. The aim of this study was to detect the role of OGG1 Ser326Cys polymorphism in susceptibility to colorectal cancer (CRC) in a Kashmiri population. We investigated the genotype distribution of the OGG1 gene in 114 CRC cases in comparison with 200 healthy subjects. There was no significant association between OGG1 Ser326Cys polymorphism and CRC, but the homozygous Cys/Cys variant genotype was associated with an increased risk of colon cancer (p<0.05). This study suggests that the OGG1 polymorphism is not associated with the risk of development of CRC in the Kashmiri population in general but modulates the risk of cancer development in colon via interaction with many dietary factors.

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

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 (APC) and ß-catenin 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 APC and ß-catenin 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 APC gene and exon 3 of the ß-catenin gene by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and/or PCR-direct sequencing. Analysis of promoter hypermethylation of the APC 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 APC 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 APC gene (p ≤ 0.05). Although the number of mutations in the APC and ß-catenin genes in our CRC cases was very low, the study confirms the role of epigenetic gene silencing of the pivotal molecular gladiator, APC, of the Wnt pathway in the development of CRC in the Kashmiri population.

Mutational profile of the CAV-1 gene in breast cancer cases in the ethnic Kashmiri population.

The role of caveolae and the caveolin proteins in cancer has been the subject of extensive research. It has been suggested that Caveolin-1 may contribute to certain steps of carcinogenesis in various types of cancer. Therefore in our study we focused on the potential clinical relevance of Caveolin-1 in 130 malignant breast tissue specimens along with their adjacent normal tissues. Using allele specific PCR we were able to rule out the mutation status of all the samples and then we did the conventional PCR-SSCP and sequencing of the mutated samples along with the normal adjacent tissues. Caveolin-1 was identified in a screen for genes involved in breast cancer progression and we demonstrated 29.2% mutational status in our Kashmiri ethnic population. We were able to detect 38 mutations out of which 22 were missense, 4 were nonsense, and 12 were frame shifts. Ten novel Cav-1 mutations (missense and frameshift). We conclude that the gene encoding CAV-1 plays an important role in the promotion of mammary tumorigenesis in Kashmir.

Caveolin-1 promotes mammary tumorigenesis: mutational profile of the Kashmiri population.

BACKGROUND: The role of caveolae and the caveolin proteins in cancer has been the subject of extensive research. It has been suggested that caveolin-1 (Cav-1) may contribute to certain steps of carcinogenesis. In the present study we focused on its potential clinical relevance in mammary malignancies. METHODS: We investigated 130 breast cancer samples along with adjacent normal tissues using allele specific PCR for the mutation status and then conventional PCR-SSCP and sequencing of mutated samples along with the normal adjacent tissues. RESULTS: Caveolin-1 was identified in a screen for genes involved in breast cancer progression and we demonstrated 29.2% mutational status in our Kashmiri ethnic population. We were able to detect 38 mutations out of which 22 were missense, 4 were nonsense, and 12 were frame shifts amongst these 38 we were also able to detect ten novel Cav-1 mutations (missense and frameshift mutations). CONCLUSION: We conclude that our study suggests that the gene encoding Cav-1 plays an important role in the promotion of mammary tumorigenesis and are associated with the development and progression of breast cancer.

A Case-Control Study of TP53 R72P Polymorphism in the Breast Cancer Patients of Ethnic Kashmiri Population.

BACKGROUND: TP53 R72P polymorphism has been proposed as a risk factor for breast cancer and is more likely to differ among different ethnic populations. We carried out the study to determine the role of R72P polymorphism in breast cancer patients of Kashmir, an ethnic population by PCR-RFLP. METHODS: To evaluate the role of this polymorphism in our ethnic Kashmiri population, we devised our study to study its role in breast cancer patients and healthy controls. The contribution of TP53 R72P polymorphism in 130 breast cancer patients and 220 female healthy controls was assessed using a PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism). RESULTS: We observed that women with PP genotype have increased risk for developing breast cancer. We found Pro/Pro genotype statistically significantly associated with dwelling, lymph node metastases, histopathological grade, and menopausal status. Pro/Pro genotype in cases and controls was observed and it was found that it is significantly associated with the breast cancer. CONCLUSIONS: Our findings suggest that TP53 R72P polymorphism is a risk factor in breast cancer. Furthermore, these results suggest Pro72 allele is associated with higher risk for breast cancer patients. Women with PP genotype have increased risk for developing breast cancer.

Mutational spectrum of conserved regions of TP53 and PTEN genes in Kangri cancer (of the skin) in the Kashmiri population.

Kangri cancer is a unique, thermally induced squamous cell carcinoma (SCC) of the skin that develops due to persistent use of a Kangri (a brazier) by the Kashmiri people to combat the cold temperature during winter. Unlike classical UV-induced SCC of the skin, Kangri cancer appears on the legs and abdomen. Its common features are erythematous patches, recurrence and metastasis. In the absence of any molecular etiology, we made a preliminary attempt to estimate the nature and frequency of mutations in the TP53 and PTEN genes in Kangri cancer patients from Kashmir. PCR-SSCP analysis followed by direct sequencing revealed that TP53 mutations account for 40% (12/30) of sporadic Kangri cancer patients and that PTEN mutations account for only 6.6% (2/30). There were 16 mutations in TP53 exons 5 and 7, found in 12 patients. They consisted of 11 substitutions (7 transitions, 3 transversions and 1 double-base) and 5 insertions. The 11 substitutions represent 8 distinct missense mutations, 3 of which were silent mutations. The mutations detected in the PTEN gene consisted of one insertion and one C>T transition. This high percentage of TP53 mutations (especially A>G) showed a statistically significant association with age and positive lymph node status. Our results indicate that TP53 is a predominant target of chronic hyperthermia in the development of Kangri cancer in the moderate risk Kashmiri population. The differences in the TP53 mutation spectrum of UV-induced SCC of the skin and Kangri cancer are probably due to the nature of the respective environmental carcinogens. The study also suggests that TP53 may function as a potential molecular marker and prognostic tool, at least in a subset of sporadic Kangri tumors.

Aberrant promoter methylation and reduced expression of p16 gene in esophageal squamous cell carcinoma from Kashmir valley: a high-risk area.

Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancer in Jammu and Kashmir region of India and has multi-factorial etiology involving dietary habits, genetic factors, and gene environmental interactions. Inactivation of the p16 gene expression by aberrant promoter methylation plays an important role in the progression of esophageal carcinoma. In the present investigation, we have studied the role of p16 promoter methylation in 69 histopathologically confirmed ESCC tissues and compared it with corresponding normal adjacent tissues for DNA methylation in the CpG island in the p16 promoter region by methylation-specific polymerase chain reaction (MSP) and p16 protein expression by immunoblotting. The results showed loss of p16 expression in 67% (46/69) of tumor tissues compared to only 3% in control tissues (2/69). Promoter methylation was observed in 52% (36/69) of tumor tissues and it gradually increased with the increasing severity of histological grades of the cancer (P = 0.0001). Loss of p16 expression with promoter methylation was observed in 26 of 36 cases (72%). Analysis of patients dietary habits revealed a strong association between promoter methylation and high consumption of hot salted tea (P < 0.05) which is a most favourite drink commonly consumed by Kashmiri people.