Bioinformatics and Experimental Analysis of the Genetic and Non-genetic Basis of Breast Cancer in Pakistani Population


Breast cancer is a multifactorial and complex disorder. It is posing serious public health concerns and its incidence rate is on the rise in Pakistan. It is therefore of prime importance to identify genetic and/or non-genetic factors contributing towards the development and progression of breast cancer. The present investigation is a case-control study including 1000 cases and 1000 age matched controls of the same ethnic background. Individuals were recruited on the basis of a predefined inclusion and exclusion criteria. All participants were in-person directly interviewed after signing an informed consent document. Peripheral blood samples were collected from all the participants along with personal identifiers, demographic characteristics and family history of cancer and other diseases. Vital status/survival status of the patients was determined for up to a maximum of 47 months to record the censored data. We analyzed our sequenced variants and clinico-pathologic features for their possible association with the disease risk by using unconditional logistic regression. Association of the variables was measured with ORs and corresponding 95% confidence intervals. Overall survival of the patients was assessed using Kaplan-Meier curve. Cox proportional hazard model was used to calculate risk ratios and to adjust for potential confounders.

A total of thirteen variants were reported in BRCA1 and BRCA2 genes respectively including three novel variants (Exon3 -37insC, Exon3 -215T

We also examined the cross-sectional associations of life style, reproductive and socio-demographic risk factors with breast cancer density in Pakistani women. Mean age of cases and controls at recruitment was 50.58±10.68 and 54.78±14.52 years while mean BMI for cases and controls was 26.07±4.04 and 25.05±4.25, respectively. Among the patients 60.70% were married, 46.50% were nulliparous, 16.90% had ≥4 children, 39.90% women breast fed their children, 88.90% were nonsmokers and 67.90% were physically active. Post-menopausal women diagnosed with breast cancer accounted for 52.30%. In the current data set, 31.70% patients had at least a blood relative diagnosed with some type of cancer, 22.80% patients were diagnosed with other types of medical complications including high blood pressure, diabetes etc. Significant association between age and breast cancer was observed. Overweight (BMI≥25) and obese (BMI≥30) females have approximately 1.5 times more risk of having breast cancer (Overweight; OR = 1.52, 95% CI: 1.28-1.81 and Obese; OR = 1.41, 95% CI: 1.14-1.74). It was also observed that unmarried women were at more than two fold higher risk. Similarly use of oral contraceptives and smoking were also significantly associated with increasing risk of breast cancer. Individuals who were physically inactive were recorded to be 1.27 times more likely to develop breast cancer. We have found approximately 1.34 fold increase in the disease risk among the postmenopausal patients (OR = 1.34, 95% CI: 1.14-1.58). Breast cancer patients were observed having an overall median survival time of 33 months (95% CI: 28-34).

In this present study we attempted to define the genetic and non-genetic basis responsible for breast cancer incidence among Pakistani population. It can be concluded that there is a significant contribution of BRCA1 and BRCA2 genetic alterations in breast cancer pathogenesis. It is hoped that our findings will be of great importance to establish adequate evidence-based awareness and preventative measures against breast cancer in Pakistani women.

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