Genetic and Computational Analysis of Tgfb1 &amp; Fgfr2 Polymorphism in Correlation to Breast Cancer Susceptibility in Pakistani Women

Uzma Shaukat Mehwish Toor

doi:10.4172/1948-5956.1000305

Abstract

Worldwide genome-wide association studies have proven very helpful in analyzing the association of susceptible breast cancer genes. In the study presenting here association of susceptible genes FGFR2 and TGFB1 to breast cancer development was explored in Pakistani population which will be helpful in determining the choice of therapy and genetic counseling for ultimately cure of the disease and better treatment. The outcome is that we analyzed 100 samples including follow up patients and found that T-C base substitution of FGFR2 rs1219648 and rs2981582 was strongly associated with the risk of breast cancer whereas the T-C base substitution of TGFB1 rs1800470 was found in some cases though not in all patients suggesting its association within specific caste Awan and Rajput belonging to Mianwali and Khushab district area and thereby elucidating weak association with breast cancer risk. In follow ups we have analyzed that patient with T nucleotide at base position 88 had showed no therapeutic response to chemotherapy i.e. taxanestamoxifen, whereas individuals with C nucleotide chemotherapy was effective. In Silico analysis revealed that mutations of FGFR2 are in intronic region. We subsequently scanned its intronic region. We subsequently scanned its intronic region and mutant structure comparison of TGFB1 with native showed drastic change in its structure having stemmed –loop which blocks the receptor site. Detailed medical history of patients revealed that in our population breast cancer is strongly associated with risk factors such as post menopause, high tea consumption and same caste of spouse and previous breast biopsy. Statistical analysis showed that the frequency of breast cancer at age greater than 40 is higher. It has also been seen that women who had children after age 30 were more susceptible to breast cancer. P value was greater than 0.1 which is not significant showing its high prevalence in our society similar to western population. Phylogenetic analysis has also been done on both genes. In FGFR2 mouse and humans are in same clusters showing close relation whereas in TGFB1 horse and chimpanzee show convergence to human. This analysis will help in choice of economical organism for pharmacogenomics to check drug response.

Highlights

Understanding the genetic mechanism of a disease often initiates with uncovering alterations that directly or indirectly causes cells to malfunction or due to various environmental factors.Breast cancer is the most commonly occurring cancer and the leading cause of cancer death among women worldwide, accounting for 27% of all cancers [1]
For Genetic association of candidate SNPs and Breast cancer susceptibility the primers of fibroblast growth factor receptor 2 (FGFR2) gene for SNP rs2981582 and rs1219648 were optimized at 55°C and of TGFB1 gene for SNP rs1800470 were at 58°C
Gel pictures of FGFR2 and TGFB1 gene are shown in Figures 1a and 1b respectively

Summary

Introduction

Understanding the genetic mechanism of a disease often initiates with uncovering alterations that directly or indirectly causes cells to malfunction or due to various environmental factors.Breast cancer is the most commonly occurring cancer and the leading cause of cancer death among women worldwide, accounting for 27% of all cancers [1]. Breast cancer is the second most common cause of death among women in Western countries [2]. For the year 2009, it was estimated that in the United States approximately 192,370 female patients would be diagnosed with breast cancer and 40,170 would die from it [3]. In developing countries such as China, the increasing trend for the Western lifestyle has been accompanied by a sharp rise on the rate of breast cancer, especially in urban areas and for those of their prime age [4]. In Pakistan out of every nine women is on risk of the disease accounting for 38.4% in country (Omar Aftab, coordinator of Pink ribbon research)

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