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.