Oral Cancer - Understanding intra-tumor heterogeneity to identify prognosis biomarkers

Overview

Project Summary

Oral squamous cell carcinoma (OSCC) is usually diagnosed in an advanced stage and associated with high recurrence and metastasis, being five-year survival in advanced disease of approximately 20%. Cancer, including OSCC, presents intertumoral and intratumoral heterogeneity, since tumors contain different subpopulations of cells either within a primary tumor or between tumors of different tissues. It is important to stress that cancer patient’s management is particularly challenging due to the presence of intra-tumor heterogeneity, which could be originated by subpopulations of distinct cells with nonrecurring mutations and (epi)genomic alterations as well as by clonal evolution and positive selective pressure from therapeutics. In OSCC the molecular heterogeneity seems also to hamper the application of precision medicine based in the knowledge of some biomarkers already identified. In this sense, this study aimed to perform a genomic and epigenetic characterization of multiregional tissue samples from the same OSCC patients to evaluate the presence of intratumor heterogeneity as well as to correlate the (epi)genomic signatures with patients ’clinicopathological features for the identification of robust prognostic biomarkers. This project addresses a relevant up-to-date subject, since OSCC is a lethal disease that remains late diagnosed, imparting serious and devastating disabilities on the survivors, having an alarming increase of incidence in younger people and the clinical strategy did not change much for the last decades, if we exclude the use of cetuximab in selected clinical settings. The results from this OSCC comprehensive (epi)genomic characterization could be essential for the guidance of treatment and clinical patient’s management as well as to direct the development of molecular target therapies and identification of the patients that could be benefited utmost with each therapeutics, leveraging the trully OSCC precision medicine

Main Goals

This project has focus on genomic and epigenetic profiling to analyze intra-tumor heterogeneity as well as to correlate these molecular signatures with clinicopathologic features of the tumors and patients in order to build prediction models of relapses/metastasis development.

The specific aims of this proposal are:

- Genomic and epigenetic characterization of multiregional tissue biopsies from the same

OSCC tumors through array comparative genomic hybridization (aCGH) and Digital Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA),respectively.

- Correlate these genomic and epigenetic signatures of the multi-biopsies from the same patients to infer about oral cancer intra-tumor heterogeneity and its relationship with therapy

response.

- Correlate the identified genomic and epigenetic signatures with the clinical- pathological

features of the tumors and patients to identify specific biomarkers and signatures with prognosis value.

- Bioinformatic integration of the obtained data with data from The Cancer Genome Atlas

(TCGA) database to validate the identified molecular signatures.

Project Details