Divergent Genomic Drivers in Benign-Appearing Lung Precursors and Their Synchronous Carcinomas.

BACKGROUND/

OBJECTIVES

How the histologically benign tier of lung preinvasive lesions-atypical adenomatous hyperplasia (AAH) and squamous dysplasia (SD)-relates genomically to its paired carcinoma is unclear. To identify early versus late events, we compared synchronous preinvasive and invasive lesions from the same patient.

METHODS

Whole-exome sequencing was performed on 33 FFPE samples from 11 patients (7 AAH-lung adenocarcinoma [LUAD] and 4 SD-squamous cell carcinoma [SqCC] pairs, with paired normal lung). FFPE artefacts were mitigated by paired-normal subtraction, panel-of-normals filtering, and orthogonal caller cross-validation. Cancer-panel variants were classified as cancer-only, shared, or preinvasive-only.

RESULTS

Only ∼10% of cancer-panel variants were shared between paired lesions (∼50% carcinoma-only, ∼40% preinvasive-only), indicating that benign AAH/SD do not broadly mirror the paired carcinoma. Within this small shared fraction, the early-driver pattern diverged between tracks: AAH-LUAD pairs tended to share EGFR alterations, whereas the four SD-SqCC pairs featured MET-pathway alterations without any shared EGFR events. TP53 and most other canonical drivers were carcinoma-confined (within-cohort contrast direction-consistent but non-significant); three patients lacked any canonical driver despite substantial mutational burden.

CONCLUSIONS

In this pilot cohort, benign AAH and SD were genomically largely distinct from their paired carcinomas, sharing only a small set of key drivers whose identity diverged between glandular and squamous tracks. This suggests that benign-appearing AAH/SD differ from the more advanced AIS/MIA precursors not only histologically but also at the genomic level. These hypothesis-generating findings require confirmation in larger, multi-omic cohorts.