Assessment of intratumoral genetic heterogeneity estimates as prognostic markers across several cancer types

• Grant number: 17/17974-9
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2017
• End date: February 28, 2019
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Pedro Alexandre Favoretto Galante
• Grantee: Filipe Ferreira dos Santos
• Host Institution: Hospital Sírio-Libanês. Sociedade Beneficente de Senhoras (SBSHSL). São Paulo , SP, Brazil

Abstract

Intratumoral genetic heterogeneity (ITH) occurs when a tumor is composed of several cellular subpopulations, which present some shared mutations and, especially, other exclusive mutations. It is known that high levels of ITH are correlated with poorer prognosis and resistance to different treatments, such as radiotherapy. Therefore, easy-to-implement, low-cost tools and a rapid assessment of ITH can make the measurement of this tumor characteristic a routine in the oncology clinic and potentially direct each patient to a more precise and effective treatment. The MATH score (mutant-allele tumor heterogeneity score) is an estimate of ITH based on the distribution of the allelic frequencies of somatic mutations in a sample. This score has the advantage of being easy to implement and inexpensive, as it is estimated through the sequencing of a single fragment of the tumor, without the need for additional evaluations about the copy number variation (CNV) or the purity of the sample, which is necessary in other methodologies. To date, high MATH scores have already been correlated with the likelihood of metastasis in colon cancer and a poorer prognosis and shorter overall survival in head and neck, liver, and breast cancers. In this study, we will use bioinformatics tools, somatic mutation data from exomes and clinical information to test if the MATH scores are sufficiently informative about the ITH of, initially, 20 tumor types of the TCGA/Pan-cancer project and are correlated with tumor prognostic parameters. In order to make this, we will compare the ITH estimates generated by MATH scores and by PyClone, which requires additional analysis and - potentially - costs, but it is still a widely used method for the evaluation of ITH. We will also attempt to optimize the potential clinical applicability of the MATH score by: (i) assessing whether MATH values estimated from cancer gene panel data are equivalent to that of whole exomes; (ii) and estimating the minimum sequencing coverage necessary to obtain robust and reproducible MATH scores. We believe that our results will indicate the ideal conditions for the application of the MATH score routinely in the clinic, something that will be of extreme value for patients and oncologists. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DOS SANTOS, FELIPE R. C.; GUARDIA, GABRIELA D. A.; DOS SANTOS, FILIPE F.; OHARA, DANIEL T.; GALANTE, PEDRO A. F.. Reboot: a straightforward approach to identify genes and splicing isoforms associated with cancer patient prognosis. NAR CANCER, v. 3, n. 2, p. 15-pg., 2021-06-01. (17/18246-7, 18/15579-8, 17/19541-2, 17/17974-9)