Genetic Alterations in Preinvasive Lung Synchronous Lesions

Area of Science:

• Genomics
• Cancer Biology
• Oncology

Background:

• Lung cancer, particularly lung adenocarcinoma (LUAD), remains a significant cause of cancer mortality globally.
• Advances in treatment have been made, yet understanding the fundamental processes of tumorigenesis is crucial.

Purpose of the Study:

• To characterize genome-wide tumorigenesis events in LUAD.
• To validate the hypothesis of multistep carcinogenesis in LUAD.
• To investigate early genetic alterations in preinvasive lesions.

Main Methods:

• Multiregion whole-exome sequencing was performed on 19 samples from three LUAD patients, including synchronous preinvasive lesions (AAH, AIS, MIA).
• RNA sequencing was used to supplement findings at the allelic variant level.
• Identification of potential pathogenic mutations present in preinvasive stages.

Main Results:

• Independent mutational profiles were observed within and between patients.
• Shared mutations, such as EGFR (p.L858R), were identified across synchronous lesions.
• Driver gene mutations were detected in atypical adenomatous hyperplasia (AAH).

Conclusions:

• Driver gene mutations in AAH support a sequential exacerbation model, aligning with Darwinian evolution of the cancer genome.
• The observed intertumoral and intratumoral heterogeneity in synchronous LUAD suggests the need for multi-biomarker treatment strategies.
• Understanding the genetic continuum of LUAD progression is key for targeted therapies.