2335P - Spatial whole exome sequencing reveals the genetic features of highly-aggressive components in lung adenocarcinoma

Background

In invasive lung adenocarcinoma (LUAD), patients with micropapillary (MIP) or solid (SOL) components had a significantly poorer prognosis than those with only lepidic (LEP), acinar (ACI) or papillary (PAP) components. It is interesting to explore the genetic features of different histologic subtypes especially the highly aggressive components.

Methods

This study comprised four cohorts of patients who underwent complete surgical resection for lung adenocarcinoma (LUAD) and had their medical records reviewed. Cohort 1 depicted the distribution of different histological subtypes across tumor size groups. Logistic regression analysis in cohort 2 investigated the associations between driver mutations and histological subtypes. Cohort 3 utilized spatial whole-exome sequencing with laser-capture microdissection to identify genetic heterogeneity among histological components within the same tumor. Cohort 4, in conjunction with the cBioportal cohort, was employed to validate the findings obtained from cohort 3.

Results

Based on a cohort of 5,933 patients (cohort 1), this study observed varying prevalence of micropapillary (MIP) and solid (SOL) components in different tumor size groups. Furthermore, cohort 2 revealed that patients with ALK fusion or TP53 mutations had a higher probability of developing MIP/SOL components in cohort 2. To account for individual differences, tspatial whole-exome sequencing was performed using laser-capture microdissection on five patients with coexistent components, enabling the identification of genetic features within the same tumor. In tracing the evolution of components, we found that titin mutation might serve as a crucial intratumor potential driver for MIP/SOL components, which was validated by the cohort 4 of 146 LUAD patients undergoing bulk WES. Functional analysis demonstrated that TTN mutations were enriched the complement and coagulation cascades, which correlated with the pathway of cell adhesion, migration, and proliferation.

Conclusions

Collectively, the histologic subtypes of invasive LUAD were genetically different, and certain trunk genotypes might synergize with branching TTN mutation to develop highly aggressive components.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.