The expression of mismatched repair genes and their correlation with clinicopathological parameters and response to neo-adjuvant chemotherapy in breast cancer

Abstract

Background: The DNA mismatch repair (MMR) pathway is an important post-replicative repair process. It is involved in the maintenance of genomic stability and MMR genes have therefore been named the proofreaders of replicating DNA. These genes repair the replicative errors of DNA and are thus imperative for genomic stability. The MMR genes have been found to be involved in promoting cytotoxicity, apoptosis, p53 phosphorylation and cell cycle arrest following exposure to exogenous DNA damaging agents. Loss of MMR function prevents the correction of replicative errors leading to instability of the genome, and can be detected by polymorphisms in micro satellites (1-6 nucleotide repeat sequences scattered in whole of the genome). This phenomenon, known as micro satellite instability (MSI), is a hallmark of MMR dysfunction and can be used as a marker of MMR dysfunction in colorectal and other malignancies. An alternative method for detection of MMR dysfunction is to test the expression of protein products of the MMR genes by immunohistochemistry (IHC), as mutations in these genes lead to reduced or absent expression of their gene products. Correlation between loss of MMR function and clinical, histopathological, behavioral parameters of the tumor and its response to chemotherapy in breast cancers may be of value in predicting tumor behavior and response to neoadjuvant chemotherapy (NACT). Neoadjuvant chemotherapy is an integral part of multimodal therapy for locally advanced breast cancer and predicting response may help in tailoring regimens in patients for optimum response. Materials: After approval by the IRB(Institutional Review Board) and ethical committee of the hospital, 31 cases of locally advanced breast carcinoma (LABC) were studied to assess the correlation between MMR dysfunction, clinicopathological parameters and objective clinical response to neoadjuvant chemotherapy using immunohistochemistry. The immunohistochemical analysis for four MMR protein products -MLH1, MSH2, MSH6 and PMS2 was done in the pre NACT trucut biopsy specimen and after three cycles of NACT with C AF (cyclophosphamide, adriamycin, 5-fluorouracil) regimen, in the modified radical mastectomy specimen. Results and conclusion: There was no significant correlation observed between expression of MMR proteins and age, family history, tumor size or histological type. However there was a statistically significant negative correlation between MLH1, MSH2 expression and histological grade. There was also a negative correlation observed between PMS2 expression after neo-adjuvant chemotherapy and clinical response. Cases with high post NACT expression of PMS2 were poor responders to chemotherapy. MSH6 was the most frequently altered MMR gene, with a negativity rate of 48% and the patients with high expression responded poorly to NACT. The study highlights the possible role of MMR expression in predicting aggressive tumor behavior (histological grade) and response to neoadjuvant chemotherapy in patients with LABC. © 2007 Chintamani et al; licensee BioMed Central Ltd.