Development and implementation of a DNA repair dysregulation score to predict response to neoadjuvant therapy in rectal cancer patients

• Grant number: 15/15246-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: February 01, 2016
• End date: January 31, 2018
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Anamaria Aranha Camargo
• Grantee: Jeffersson Leandro Jimenez Restrepo
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil

Abstract

AbstractRectal cancer affects the final portion of the large intestine. Standard treatment for rectal cancer involves the use of neoadjuvant radio chemotherapy (RCTneo) followed by surgical removal of residual tumor. This procedure confers a better local control of the disease and higher chances of sphincter function preservation. However, the response to RCTneo varies significantly among patients. While some patients have complete tumor regression after RQTneo, others have minimal regression. Nonetheless, it is not possible to determine at diagnosis which patients will experience good response and benefit from RCTneo and more conservative surgical interventions, and which patients will experience poor response to treatment, being unnecessarily exposed to the adverse effects of RQTneo. In recent years, global analysis of gene expression were carried out by different groups in an attempt to identify sets of differentially expressed genes (Gene signatures) able to predict the response to RCTneo in patients with rectal tumor. However, the signatures identified so far were highly dependent on the samples from which they were generated, presenting with low specificity and sensitivity when tested in independent sets of samples. Recently, a new approach was introduced to identify gene signatures capable of predicting the response to treatment: the dysregulation scores of biological pathways. In contrast to traditional gene signatures, generally composed of dozens of genes unrelated functionally, dysregulation scores are composed of a small number of genes (<10), functionally related and possibly associated with the therapeutic response, for example, genes in DNA repair and apoptosis pathways. In this context, our study aims to test the utility of DNA repair dysregulation scores developed for melanoma, lung and ovary tumors, as well as to develop our own dysregulation score based on the expression pattern of genes from different DNA repair pathways to predict the response to RCTneo in patients with rectal cancer. (AU)