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Intratumoral genetic heterogeneity and defective DNA repair mutational signatures as predictive biomarkers of response to nCRT in Rectal Cancer patients

Grant number: 20/11204-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2020
Effective date (End): August 31, 2021
Field of knowledge:Health Sciences - Medicine - Surgery
Principal researcher:Rodrigo Oliva Perez
Grantee:Franciele Hinterholz Knebel
Home Institution: Hospital de Beneficência Portuguesa de São Paulo. Real e Benemérita Associação Portuguesa de Beneficência de São Paulo (RBAPB). São Paulo , SP, Brazil
Associated research grant:18/15582-9 - Complete tumor regression in rectal cancer patients after neoadjuvant chemoradiation: molecular prediction of tumor response based on intratumoral heterogeneity and assessment of response by circulating tumoral DNA, AP.JP2

Abstract

Neoadjuvant chemoradiation (nCRT) is the preferred initial treatment strategy for Distal Rectal Cancer. nCRT may lead to significant primary tumor regression in these patients and eventually to complete pathological response (pCR). Clinical, endoscopic and radiological features have been used to identify patients with pCR to avoid potentially unnecessary radical surgery and its associated morbidity, mortality and functional consequences (urinary, sexual and anorectal). These patients could be enrolled in organ- preserving strategies without immediate surgical resection of the rectum. However, this organ-preserving approach has 2 main limitations: the absence of predictive tests for the response to nCRT and significant subjectivity/inaccuracy in clinical, endoscopic and radiological assessment of response. Rectal Cancers exhibit significant intratumoral heterogeneity (ITGH). There is a direct association between the levels of ITGH and primary disease stage. The present study aims to: 1- establish a correlation between ITGH and response to nCRT; 2- characterize the mutational signatures of rectal tumors presenting complete and incomplete response to nCRT; and 3- evaluate the association between ITGH and defective DNA repair signatures and response to nCRT. (AU)

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