Racial Diversity and Co-Mutational Analysis of Biologically Relevant Alterations in EGFR Mutant Lung Cancers

Document Type

Article

Publication Date

6-1-2025

Publication Title

Clinical lung cancer

Keywords

Aged, Female, Humans, Male, Middle Aged, Biomarkers, Tumor, Black or African American, DNA Copy Number Variations, DNA Mutational Analysis, ErbB Receptors, Lung Neoplasms, Mutation, White, Racial Groups

Abstract

BACKGROUND: EGFR alterations have significant therapeutic implications in lung cancer (LCa), yet their prevalence and co-mutational patterns in African American populations remain understudied. This study analyzes EGFR-mutant LCa across races using the Tempus database.

METHODS: De-identified records sequenced via Tempus xT assay, (595 to 648 gene DNA panel) were included if they had ≥ 1 pathogenic EGFR mutation (short variants (SVs), copy number amplifications (CNAs), or fusions). Race was determined based on recorded clinical records. Co-mutations were restricted to genes with ≥ 5% frequency in at least 1 race. Statistical analyses were performed using chi-squared tests with Bonferroni or false discovery rate adjustments for multiple testing.

RESULTS: Among 17,482 LCa samples, EGFR alterations occurred in 8.9% of CA, 7.6% of BAA, 39% of API, 15% of other races, and 12% of unknown races. Exon 19 deletions (P = .017) and L858R mutations (P < .001) varied by race, with higher L858R frequency in CA compared to BAA (P = .034) and in API compared to CA (P = .006). EGFR copy number variants (CNVs) were highest in BAA (P < .001). TP53 alterations occurred at a higher frequency in patients with a history of smoking, those with high tumor mutational burden (TMB), and high PD-L1. KMT2C co-mutations were significantly more common in BAA (13%) compared to CA (3%) and API (4%) (q = 0.003). Similarly, GLI1 co-mutations were most frequent in BAA (5.8%) compared to 1.5% in CA and 0% in API patients (q = 0.025).

CONCLUSIONS: EGFR mutation subtypes and co-mutations differ by race. KMT2C may influence TMB and immunotherapy response, while GLI1 is linked to TKI resistance. TP53 alterations were more commen in smokers, and patients with high PDL-1 and TMB, highlighting additional factors that drive tumors with these alterations.

Medical Subject Headings

Aged; Female; Humans; Male; Middle Aged; Biomarkers, Tumor; Black or African American; DNA Copy Number Variations; DNA Mutational Analysis; ErbB Receptors; Lung Neoplasms; Mutation; White; Racial Groups

PubMed ID

40064574

ePublication

ePub ahead of print

Volume

26

Issue

4

First Page

307

Last Page

313

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