Lung squamous cell carcinomas with basaloid histology represent a specific molecular entity

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Basaloid carcinoma and its variants within lung squamous cell carcinoma (SCC) present a poor prognosis.
• The specific molecular drivers and effective therapeutic strategies for basaloid SCC remain largely unknown.

Purpose of the Study:

• To investigate the distinct molecular characteristics of basaloid SCC compared to other lung SCC subtypes.
• To identify potential diagnostic markers and therapeutic targets for basaloid SCC.

Main Methods:

• Genome-wide analysis of DNA copy number aberrations and mRNA expression profiles in 93 lung SCC samples, including 42 basaloid tumors.
• Development of a 2-gene (SOX4, IVL) immunohistochemistry-based predictor for basaloid tumor identification.
• Validation of the molecular subtype and its prognostic significance across multiple independent datasets.

Main Results:

• Pure basaloid tumors exhibit a unique mRNA expression profile associated with stem cell and germline factors, and underexpression of squamous differentiation genes.
• The 2-gene predictor accurately distinguished basaloid SCCs from non-basaloid SCCs with 94% accuracy.
• The basaloid SCC molecular subtype was identified in independent datasets and strongly correlated with significantly poorer survival (adjusted HR = 2.45).

Conclusions:

• Basaloid SCC represents a distinct histomolecular subtype of lung SCC, warranting separate classification.
• The identified molecular profile suggests inherent resistance to conventional chemotherapy.
• This molecular signature provides a basis for developing novel targeted therapies for basaloid SCC.