PTEN Genetic and Epigenetic Alterations Define Distinct Subgroups in North Indian Breast Cancer Patients

Abstract

Background: Breast cancer is a heterogeneous disease that can be subdivided on the basis of histopathological<br />features, genetic alterations, and gene-expression profiles. PTEN gene is considered an established tumor suppressor gene<br />in different types of cancer including breast cancer. However, the role of PTEN alterations in north Indian breast cancer<br />has not been explored especially in defining a group with distinct histological factors. Methodology: 181 sporadic breast<br />cancer and their adjacent normal tissues were included in the present study. We analyzed methylation and LOH through<br />MS-PCR and microsatellite markers respectively. While, for PTEN protein expression, we used immunohistochemistry.<br />All the molecular findings were correlated with the clinicopathological parameters of the patients to underline clinical<br />relevance. Results: We found that LOH and methylation of the PTEN promoter were significantly associated with<br />loss of PTEN protein expression, while, PTEN mutation was a rare event. Furthermore, out of 46 double hit cases (i.e.,<br />having both methylation and LOH), 70% (32/46) cases showed complete loss of PTEN expression (P= 0.0249). Both<br />LOH and PTEN promoter methylation were associated significantly with age and clinical stage, while, methylation<br />and loss of PTEN expression were associated with high grade and Her-2 negativity. In addition, a quadruple (ER/PR/<br />Her-2 and PTEN) negative group with distinct features was found. Conclusion: The pattern of PTEN expression and<br />its correlation with the clinical parameters indicates that loss of PTEN expression defines a clinical group with distinct<br />features. Hence, PTEN expression provides differential therapeutic strategies for north Indian breast cancer.