Dataset Information

Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.

ABSTRACT: Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in EGFR, KRAS, and STK11. A local Native American ancestry risk score was more strongly correlated with EGFR mutation frequency compared with global ancestry correlation, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. SIGNIFICANCE: The frequency of somatic EGFR and KRAS mutations in lung cancer varies by ethnicity, but we do not understand why. Our study suggests that the variation in EGFR and KRAS mutation frequency is associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association.See related commentary by Gomez et al., p. 534.This article is highlighted in the In This Issue feature, p. 521.

SUBMITTER: Carrot-Zhang J

PROVIDER: S-EPMC7933062 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.

Carrot-Zhang Jian J Soca-Chafre Giovanny G Patterson Nick N Thorner Aaron R AR Nag Anwesha A Watson Jacqueline J Genovese Giulio G Rodriguez July J Gelbard Maya K MK Corrales-Rodriguez Luis L Mitsuishi Yoichiro Y Ha Gavin G Campbell Joshua D JD Oxnard Geoffrey R GR Arrieta Oscar O Cardona Andres F AF Gusev Alexander A Meyerson Matthew M

Cancer discovery 20201202 3

Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden, and specific driver mutations in EGFR, KRAS, and STK11. A local Native American ancestry risk score was more strongly correlated with EGFR mutation frequency compared with global ancestry correlation, s ...[more]

PMID: 33268447

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Project description:Ancestry informative markers (AIMs) are used in forensic genetics to infer biogeographical ancestry (BGA) of individuals and may also have a prominent role in future police and identification investigations. In the last few years, many studies have been published reporting new AIM sets. These sets include markers (usually around 100 or less) selected with different purposes and different population resolutions. Regardless of the ability of these sets to separate populations from different continents or regions, the uncertainty associated with the estimates provided by these panels and their capacity to accurately report the different ancestral contributions in individuals of admixed populations has rarely been investigated. This issue is addressed in this study by evaluating different AIM sets. Ancestry inference was carried out in admixed South American populations, both at population and individual levels. The results of ancestry inferences using AIM sets with different numbers of markers among admixed reference populations were compared. To evaluate the performance of the different ancestry panels at the individual level, expected and observed estimates among families and their offspring were compared, considering that (1) the apportionment of ancestry in the offspring should be closer to the average ancestry of the parents, and (2) full siblings should present similar ancestry values. The results obtained illustrate the importance of having a good balance/compromise between not only the number of markers and their ability to differentiate ancestral populations, but also a balanced differentiation among reference groups, to obtain more precise values of genetic ancestry. This work also highlights the importance of estimating errors associated with the use of a limited number of markers. We demonstrate that although these errors have a moderate effect at the population level, they may have an important impact at the individual level. Considering that many AIM-sets are being described for inferences at the individual level and not at the population level, e.g., in association studies or the determination of a suspect's BGA, the results of this work point to the need of a more careful evaluation of the uncertainty associated with the ancestry estimates in admixed populations, when small AIM-sets are used.

Project description:BackgroundLatin America's diverse genetic makeup, shaped by centuries of admixture, presents a unique opportunity to study Alzheimer's disease dementia (AD) and frontotemporal dementia (FTD). Our aim is to identify genetic variations associated with AD and FTD within this population.MethodsThe Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLat) recruited 2,162 participants with AD, FTD, and healthy controls from six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico, and Peru). All participants underwent array, exome, and/or whole-genome sequencing. Population structure was analyzed using Principal Component Analysis and ADMIXTURE, projecting the ReDLat population onto the 1000 Genomes Project database. To identify genes associated with autosomal dominant, autosomal recessive, or X-linked forms of adult-onset dementia, we searched the Online Mendelian Inheritance in Man database and analyzed pedigree information. Variant interpretation followed guidelines from the American College of Medical Genetics and Genomics, and the Guerreiro algorithm was applied for the PSEN1 and PSEN2 genes.ResultsGlobal ancestry analysis of the ReDLat cohort revealed a predominant mix of American, African, and European ancestries. Uniquely, Brazil displayed an additional East Asian component accurately reflecting the historical admixture patterns from this region. We identified 17 pathogenic variants, a pathogenic C9orf72 expansion, and 44 variants of uncertain significance. Among our cohort, 70 families exhibited autosomal dominant inheritance of neurodegenerative diseases, with 48 families affected by AD and 22 by FTD. In families with AD, We discovered a novel variant in the PSEN1 gene, c.519G>T (p.Leu173Phe), along with other previously described variants seen in the region, such as c.356C>T (p.Thr119Ile). In families with FTD, the most commonly associated gene was GRN, followed by MAPT. Notably, we identified a patient meeting criteria for FTD who carried a pathogenic variant in SOD1, c.388G>A (p.Phe21Leu), which had previously been reported in another FTD patient from the same geographical region.ConclusionsThis study provides the first snapshot of genetic contributors to AD and FTD in a multisite cohort across Latin America. It will be critical to evaluate the generalizability of genetic risk factors for AD and FTD across diverse ancestral backgrounds, considering distinct social determinants of health and accounting for modifiable risk factors that may influence disease risk and resilience across different cultures.

Dataset Information

Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.

Publications

Genetic Ancestry Contributes to Somatic Mutations in Lung Cancers from Admixed Latin American Populations.

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