WCLC 2025 - Posters & ePosters-P3.03.36 Whole Genome Doubling Drives Genomic Instability and Poor Postoperative Outcomes in Stage I Driver-Negative Lung Adenocarcinoma

P3.03.36 Whole Genome Doubling Drives Genomic Instability and Poor Postoperative Outcomes in Stage I Driver-Negative Lung Adenocarcinoma

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This study investigates the impact of whole genome doubling (WGD) on clinical outcomes in patients with stage I driver-negative lung adenocarcinoma (DN-LUAD), a group typically lacking actionable mutations and not considered for perioperative chemotherapy despite a 30–40% recurrence risk post-surgery. Among 77 stage I DN-LUAD patients analyzed via whole-genome sequencing and RNA sequencing, WGD was prevalent in 46.8% of cases.<br /><br />Key findings include that WGD-positive tumors exhibited significantly higher tumor mutational burden (TMB), copy-number alterations, and structural variant loads compared to non-WGD tumors. TP53 mutations were more frequent in WGD tumors, and CDKN2A copy-number loss was also more common. Clinically, WGD presence correlated with substantially worse recurrence-free survival (RFS) and a trend toward poorer overall survival (OS), despite early-stage disease. Remarkably, the co-occurrence of TP53 mutation with WGD identified a subgroup with the highest risk—showing significantly shorter RFS and OS—whereas TP53 mutation alone without WGD did not markedly elevate recurrence risk compared to TP53-wildtype tumors.<br /><br />Gene-set enrichment analyses in WGD tumors revealed upregulation of DNA repair and cell-cycle pathways, indicative of heightened genomic instability driving poor outcomes. Baseline clinicopathologic factors did not significantly differ between WGD and non-WGD groups, suggesting the genomic changes rather than clinical features underlie prognosis.<br /><br />These findings position WGD as an early and critical biomarker of aggressive disease in stage I DN-LUAD, especially when combined with TP53 mutation. The study suggests that identifying WGD status could refine risk stratification, guiding intensified perioperative treatments and closer surveillance to improve patient outcomes. Overall, WGD represents a potent genomic hallmark linked to chromosomal instability and adverse prognosis in early-stage driver-negative lung adenocarcinoma.

Asset Subtitle

Masahiro Torasawa

Meta Tag

Speaker Masahiro Torasawa

Topic Tumor Biology – Translational Biology

Keywords

whole genome doubling

WGD

stage I lung adenocarcinoma

driver-negative lung adenocarcinoma

DN-LUAD

tumor mutational burden

TP53 mutation

CDKN2A copy-number loss

recurrence-free survival

genomic instability