Abstract 6156: Deciphering the genomic landscape of Chilean cancer: Unveiling driver pathway divergence, and novel germline and actionable somatic variants
Authors: González Evelin , Toro Jessica , Blanco Alejandro , Tapia Camilo , Rivas Solange , Erices José , Osorio Felipe , Sepúlveda-Hermosilla Gonzalo , Freire Matias , Gárate Valentina , Cáceres-Molina Javier , Gallegos Iván , Barajas Olga , Ahumada Mónica , Bustamante Eva , González Jaime , Ibañez Carolina , Corvalan Alejandro , Owen Gareth , Garrido Marcelo , Armisen Ricardo , Marcelain Katherine 
Published: March 2024

Advances in understanding the genetic landscape of cancer have paved the way for more precise molecular profiling and the development of more efficacious therapeutic options. However, underrepresentation in clinical research endeavors has left the Latin American population uncharacterized, which may prevent them from reaping the benefits of these advancements. This study sought to identify the genetic drivers and actionable mutations in solid tumors from Chilean patients, enhancing our understanding of the mutational landscape in a population with a genetically diverse background shaped by admixture.Methods: 468 biopsy tissues from gastric (171), gallbladder (91), breast (72), Ovarian (69), and colorectal (65) Chilean cancer patients were collected in several pathology services and biobank at Universidad de Chile. Target-sequencing was performed using Oncomine Comprehensive Assay v.1 and v.3; and TumorSec cancer panel. Data from TCGA, MSK-IMPACT, and ACCR GENIE cohorts was accessed through cBioportal and used for comparison with non-Hispanic populations. Variants were annotated with CGI, CancerVar, OncoKB, and ClinVar tools.Results: Overall, tumors have mutations mainly in TP53 (42.4%), PIK3CA (12.5%), KRAS (9.6%), PTEN (4.7%), BRCA1/2 (9%). Driver mutations were present in TP53 (42%), PIK3CA (16%), KRAS (10%), ERBB2 (7%), PTEN (7%), BRCA1/2 (8%), ATM (7%), among others. Accionable mutations were found primarily in PIK3CA (17%), KRAS (10%), ERBB2 (9%), and NTRK1/2/3 (4.8%). Besides already-known mutations, many “novel” mutations were also found in all tumor types. About 5-15% of novel variants were predicted drivers, including variants in CDH1, NOTCH1, BRCA1/2, MTOR, TSC2, and MSH2 genes. Significantly, key driver mutations identified in non-Hispanic patients from international cohorts are also prevalent in admixed Chilean patients. However, variations at the driver pathway level were also observed. Notably, the PI3K and MTOR pathways were more frequently affected in Chilean CRC and GBC, respectively. Furthermore, mutations in specific genes, such as TP53 in GBC, were associated with Amerindian genetic ancestry.The observed differences could be attributed to the abundance of newly identified driver-predicted variants, though the possibility of the admixed genetic background influencing the oncogenic process in various tissue types cannot be excluded.

Citation Format: Evelin González, Jessica Toro, Alejandro Blanco, Camilo Tapia, Solange Rivas, José Erices, Felipe Osorio, Gonzalo Sepúlveda-Hermosilla, Matias Freire, Valentina Gárate, Javier Cáceres-Molina, Iván Gallegos, Olga Barajas, Mónica Ahumada, Eva Bustamante, Jaime González, Carolina Ibañez, Alejandro Corvalan, Gareth Owen, Marcelo Garrido, Ricardo Armisen, Katherine Marcelain. Deciphering the genomic landscape of Chilean cancer: Unveiling driver pathway divergence, and novel germline and actionable somatic variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6156.