Biology subjects

McElderry, J. P.

Publications and source records attributed to McElderry, J. P..

4 recordsLinked to original sources

bioRxiv2025

Revealing the Drivers Underlying Distinct Evolutionary Trajectories in Lung Adenocarcinoma

Elucidating the evolution of cancers allows us to understand their key events, and the order in which they occur. To chart and interpret these evolutionary trajectories, we leverage whole-genome sequencing of lung tumours, including those from the largest cohort to date of lung cancers in subjects who have never smoked. Through ordering frequent genomic alterations, we discover three distinct evolutionary paths taken by lung adenocarcinomas; two dominated by tumours from people who have never smoked (NS-LUAD), and one followed by the vast majority of those who have smoked (S-LUAD). However, one in six NS-LUAD follow the smoking-dominant trajectory. These tumours, surprisingly, have fewer somatic alterations than the other NS-LUAD, and have shorter latency. They are strongly enriched for KRAS mutations. Our results suggest that gaining KRAS mutations allows these tumours to evolve more rapidly, acquiring a set of smoking-associated key alterations, with less need for genomic instability to progress. These tumours are three times more frequent in subjects of European vs. East Asian ancestry. These findings could shape clinical management strategies for lung adenocarcinoma patients, particularly for tumours driven by smoking-like evolutionary trajectories.

cancer biology↗

bioRxiv2025

A prognostic signature for lung adenocarcinoma in people who have never smoked

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. Steady, marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes alterations, is linked to prolonged survival and low immune evasion. Proliferative shows high proliferation markers, TP53 mutations, and gene fusions. Chaotic, with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings. SignificanceThe transcriptome of 684 lung adenocarcinomas in people who have never smoked (NS-LUAD) identifies three subtypes with different cellular dynamics, and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a clinically applicable tool for treatment decision making in NS-LUAD patients.

genomics↗

bioRxiv2025

Examining the Role of Extrachromosomal DNA in 1,216 Lung Cancers

The role of extrachromosomal DNA (ecDNA) in lung cancer, particularly in subjects who never smoked (LCINS), remains unclear. Examination of over 1200 whole-genome-sequenced lung cancers identified ecDNA in 18.9% of patients. Recurrent amplification of MDM2 and other oncogenes via ecDNA possibly drives a LCINS subset. Tumors harboring ecDNA showed worse overall survival than tumors harboring other focal amplifications. A strong association with whole-genome doubling suggests most ecDNA reflects genomic instability in treatment-naive lung cancer.

bioinformatics↗

bioRxiv2025

Deciphering lung adenocarcinoma evolution and the role of LINE-1 retrotransposition

Understanding lung cancer evolution can identify tools for intercepting its growth. In a landscape analysis of 1024 lung adenocarcinomas (LUAD) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUAD that displayed diverse clonal architecture. In this group, we observed an interplay between mobile elements, endogenous and exogenous mutational processes, distinct driver genes, and epidemiological features. Our results revealed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry, and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations in KRAS plus short subclonal diversification. LUAD in never smokers showed early occurrence of copy number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumors harboring EGFR mutations exhibited long latency, particularly in females of European-ancestry (EU_N). In EU_N, EGFR mutations preceded the occurrence of other driver genes, including TP53 and RBM10. Tumors from Asian never smokers showed a short clonal evolution and presented with heterogeneous repetitive patterns for the inferred mutational order. Importantly, we found that the mutational signature ID2 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumors with ID2 showed short latency and high L1 retrotransposon activity linked to L1 promoter demethylation. These tumors exhibited an aggressive phenotype, characterized by increased genomic instability, elevated hypoxia scores, low burden of neoantigens, propensity to develop metastasis, and poor overall survival. Re-activated L1 retrotransposition-induced mutagenesis can contribute to the origin of the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

genomics↗