Relative Incidence and Molecular Analysis of Breast Cancer in Kashmiri population

Breast cancer is the third most common tumor in the world and represents 9% of global cancer burden. In India, breast cancer is the second common cancer in women after cervical cancer and has of late replaced cervical cancer as the leading site of cancer among women in Indian cities. Preliminary indications point towards an increasing trend in the occurrence of breast cancer amongst Kashmiri population. However, authentic data with regard to prevalence is almost non-existent in the state of Jammu and Kashmir. To our knowledge, this is the first attempt to examine the epidemiological distribution of different cancer typ es with particular emphasis on breast cancer in the wh ole valley. The source of our data include cancer registry in the Department of Radiation Oncology, Sheri -Kashmir Institute of Medical Sciences, Srinagar, and Department of Radiation Oncology, SMHS, Srina gar during Jan 2002 to Dec 2006 . A total of 6943 cas es registered between 1st January 2002 to 31st December 2006 comprised of 4345 males and 2598 females. The age standardized incidence rates were 34.9 per 100,000 for males an d 24.8 per 100,000 for females. Oesophagus was the leading site of cancer in both the sexes (male ASR 11.2; female ASR 8.3) followed by lung (ASR 6.5), brain (ASR 2.2), head and neck (ASR 2.2) in males and breast (ASR 5.2), skin (ASR 1.6) and rectum (ASR 0.95) in females. The incidence of cervical cancer turned out to be surprisingly lo w in Kashmir i women as compared to other Indian Registries quite contrary to the pattern in rest of the country. Our studies imply that cancer incidence was significantly lower and cancer patterns were markedly different in Kashmir. The observed cancer pattern indicates that awareness campaigns, life style and dietary habit changes, tobacco -control measures and early detection of breast cancer are very important for cancer control in this cohort of population. Abstract 2 Section II Abstract Environmental and genetic factors are attributed to explain the spectrum of geographical and ethnic variations in the development and pathogenesis of disease. The genesis of disease has been further complexed by involvement of number of genes with small effe cts and above all by population heterogeneity. Accordingly variations in genes like Brca1/Brca2 that have been strongly associated with breast cancer phenotype present a scattered mutational pattern in different populations. This study attempts to analyze the frequently mutated exons of BRCA2 for sequence variations in surgically resected breast cancer tissue samples, from a high risk ethnic Kashmiri population. PCR followed b y direct sequencing revealed presence of five variations, with four somatic mutat ions located on exon 11 and one germline variation located in UTR region of exon 2 at contig position 13870572 (rs1799943). All the four somatic mutations comprised of substitutions; two representing missense mutations leading to amino -acid substitution at codon positions 868 (novel) and 991 whereas other two were silent mutations at codon positions 846 and 1131. Codons for amino-acid positions 846 (TCC/TCA) and 868 (CCT/ACT) were seen to be present in heterozygous state in normal breast tissue samples and the heterozygous nature of both the codons was seen to be lost i n associated tumor samples in 44 out of 50 patients. Incidentally these two mutations were always found to be linked.No sequence variations were observed in exons 9, 18, 20 and 25. Gap -junction gene C onnexin 43, which codes fo r a 43 -kd gap -junction protein is a predominantly expressed gap junction protein in normal breast tissue and plays an important role in normal mammogenesis, lactogenesis and involution. Studies have shown down- re gulation of connexin 43 gap -junction protein is involved in primary tumor formation as well as metastasis in breast cancer patients and restoration of gap-junction intercellular communication by up-regulation of Abstract 3 connexins has been shown to restore normal phenotypes in vitro and reduce tumor growth in vivo . However the molecular mechanisms behind these processes remain elusive and a better understanding of the key events is necessary to gain information relevant to the designing of anti -cancer treatment models against breast cancer. In this study, coding sequence of C onnexin 43 was analyzed for polymorphic changes to establish its role (if any) in breast cancer in this cohort of population. After sequence analysis, none of the screened samples reveal ed any kind of variations in early or advanced stage of the disease. The findings from this study add to the body of knowledge about mutation prevalence and nature of different breast cancer pre -disposing genes in ethnic Kashmiri population, and may inform strategies for genetic cancer risk assessment. Our studies also imply that mutational deactivation does not play any role in the down regulation of Connexin 43 expression in Kashmiri breast cancer patients. Instead, some other regulatory mechanism like hypermethylation or mutati on of the promoter region of thegene may be involved. Additionally increased understanding of breast carcinoma pathways may enhance our ability to device targeted approaches to the preve ntion of diseas