Abstract 1005: Germline-somatic interactions in non-small cell lung cancer (NSCLC) patients from Latin America
Journal
Cancer Research
ISSN
0008-5472
Date Issued
2025-04-21
Author(s)
Garrido, Javiera
González, Evelin
Blanco, Alejandro
Sepúlveda-Hermosilla, Gonzalo
Freire, Matías
Marcelain, Katherine
Owen, Gareth I.
Ibañez, Carolina
Corvalán, Alejandro
Garrido, Marcelo
Assar, Rodrigo
Lizana, Rodrigo
Cáceres-Molina, Javier
Ampuero, Diego
Ramos, Liliana
Pérez, Paola
Aren, Osvaldo
Fernández, Cristina
Spencer, María Loreto
Flores, Jacqueline
Bernal, Giuliano
Olea, Mónica Ahumada
Rasse, Germán
Sánchez, Carolina
Galli de Amorim, Maria
Dias-Neto, Emmanuel
Freitas, Helano C.
Type
Article
Abstract
Motivation:
Tumors of non-small cell lung cancer (NSCLC) patients are heterogeneous entities. Genomic landscapes are influenced by genetic constitution, environmental exposures and the complex interaction between the two. In particular, it has been reported that germline variability specific to Latin American (LA) populations play an important role modulating the presence of acquired somatic alterations in EGFR and KRAS, two of the most clinically relevant actionable genes for lung cancer (LC). The influence of these specific genetic differences appears to be independent of smoking status, a key exogenous agent also known to influence LC genomic heterogeneity. However, LA patients are strikingly diverse and further studies are needed to better understand the influence of germline-somatic interaction on tumor variability across populations with different patterns of environmental exposures.
Methodology:
The population derived from the study protocol Characterization and Validation of Molecular Diagnostic Technologies for LC Patients from Chile, Brazil, and Peru (clinicaltrials.gov NCT03220230). The recruitment period was July 2015 to October 2018 and encompassed 37 centers. From NSCLC samples, genomics profiles were assessed using the Oncomine Focus Assay (OFA), with QC-approved assays obtained for 1864 subjects. Relevant covariates were interrogated at enrollment. In the absence of matched normal tissue samples, an in-house algorithm was developed to distinguish germline from somatic variation. Descriptive statistics, Principal Component Analyses (PCA) and logistic regression were used to evaluate germline-somatic interactions.
Results
and Conclusions: The in-house algorithm detected 738 unique germline variants and 6636 unique somatic alterations. The majority of the germline variants (80.8%, n=597) are reported in other populations with a Minor Allele Frequency (MAF) ≥ 1%; only a minority (19.1%, n=141) report a MAF either <1% or unknown. These rare germline variants are present in 98 study participants (5.3%) and are more common in the group of Chilean smoker patients with adenocarcinoma and advanced disease, and without a personal and family history of cancer (FHC). Statistical significance was found for cancer stage (stage IV: 80.8% [n=63] vs. 70.8% [n=823], p-value<0.05) and FHC (positive: 20.5% [n=16] vs. 31.9% [n=371], p-value<0.05). Regarding the relationship between germline and somatic alterations, we found a positive association for EGFR, PIK3CA, ALK, FGFR4 and ERBB2 and a negative association for the remaining genes (n=46). These findings provide novel insights into the influence of inherited genetic variability on the clinical presentation and somatic landscape of an underrepresented population. Identification of the underlying germline alleles can improve our understanding of the affected biological pathways for the subset of LCs driven by these alterations.
Citation Format:
Javiera Garrido, Evelin González, Alejandro Blanco, Gonzalo Sepúlveda-Hermosilla, Matías Freire, Solange Rivas, Katherine Marcelain, Gareth I. Owen, Carolina Ibañez, Alejandro Corvalán, Marcelo Garrido, Rodrigo Assar, Rodrigo Lizana, Javier Cáceres-Molina, Diego Ampuero, Liliana Ramos, Paola Pérez, Osvaldo Aren, Cristina Fernández, María Loreto Spencer, Jacqueline Flores, Giuliano Bernal, Mónica Ahumada Olea, Germán Rasse, Carolina Sánchez, Maria Galli de Amorim, Emmanuel Dias-Neto, Helano C. Freitas, NIRVANA team, Ricardo Armisén. Germline-somatic interactions in non-small cell lung cancer (NSCLC) patients from Latin America [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1005.
Tumors of non-small cell lung cancer (NSCLC) patients are heterogeneous entities. Genomic landscapes are influenced by genetic constitution, environmental exposures and the complex interaction between the two. In particular, it has been reported that germline variability specific to Latin American (LA) populations play an important role modulating the presence of acquired somatic alterations in EGFR and KRAS, two of the most clinically relevant actionable genes for lung cancer (LC). The influence of these specific genetic differences appears to be independent of smoking status, a key exogenous agent also known to influence LC genomic heterogeneity. However, LA patients are strikingly diverse and further studies are needed to better understand the influence of germline-somatic interaction on tumor variability across populations with different patterns of environmental exposures.
Methodology:
The population derived from the study protocol Characterization and Validation of Molecular Diagnostic Technologies for LC Patients from Chile, Brazil, and Peru (clinicaltrials.gov NCT03220230). The recruitment period was July 2015 to October 2018 and encompassed 37 centers. From NSCLC samples, genomics profiles were assessed using the Oncomine Focus Assay (OFA), with QC-approved assays obtained for 1864 subjects. Relevant covariates were interrogated at enrollment. In the absence of matched normal tissue samples, an in-house algorithm was developed to distinguish germline from somatic variation. Descriptive statistics, Principal Component Analyses (PCA) and logistic regression were used to evaluate germline-somatic interactions.
Results
and Conclusions: The in-house algorithm detected 738 unique germline variants and 6636 unique somatic alterations. The majority of the germline variants (80.8%, n=597) are reported in other populations with a Minor Allele Frequency (MAF) ≥ 1%; only a minority (19.1%, n=141) report a MAF either <1% or unknown. These rare germline variants are present in 98 study participants (5.3%) and are more common in the group of Chilean smoker patients with adenocarcinoma and advanced disease, and without a personal and family history of cancer (FHC). Statistical significance was found for cancer stage (stage IV: 80.8% [n=63] vs. 70.8% [n=823], p-value<0.05) and FHC (positive: 20.5% [n=16] vs. 31.9% [n=371], p-value<0.05). Regarding the relationship between germline and somatic alterations, we found a positive association for EGFR, PIK3CA, ALK, FGFR4 and ERBB2 and a negative association for the remaining genes (n=46). These findings provide novel insights into the influence of inherited genetic variability on the clinical presentation and somatic landscape of an underrepresented population. Identification of the underlying germline alleles can improve our understanding of the affected biological pathways for the subset of LCs driven by these alterations.
Citation Format:
Javiera Garrido, Evelin González, Alejandro Blanco, Gonzalo Sepúlveda-Hermosilla, Matías Freire, Solange Rivas, Katherine Marcelain, Gareth I. Owen, Carolina Ibañez, Alejandro Corvalán, Marcelo Garrido, Rodrigo Assar, Rodrigo Lizana, Javier Cáceres-Molina, Diego Ampuero, Liliana Ramos, Paola Pérez, Osvaldo Aren, Cristina Fernández, María Loreto Spencer, Jacqueline Flores, Giuliano Bernal, Mónica Ahumada Olea, Germán Rasse, Carolina Sánchez, Maria Galli de Amorim, Emmanuel Dias-Neto, Helano C. Freitas, NIRVANA team, Ricardo Armisén. Germline-somatic interactions in non-small cell lung cancer (NSCLC) patients from Latin America [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1005.