Lung Squamous Cell Carcinomas with Basaloid Histology Represent a Specific Molecular Entity

Abstract

Purpose: The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient.Experimental Design: To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed).Results: Supervised analyses reveal that pure basaloid tumors display a specific mRNA expression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n ¼ 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjusted HR ¼ 2.45; P ¼ 0.000001).Conclusion: This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies. Clin Cancer Res; 20(22); 5777-86. Ó2014 AACR.

MicroRNAs associated with lung squamous cell carcinoma: New prognostic biomarkers and therapeutic targets

“…Proteoglycans have an indispensable role in the tumor microenvironment, and as a result, many studies have described their potential use as target genes, biomarkers, and active agents . Moreover, it has been found that mutations in cell cycle genes can affect the differentiation of squamous cells in the course of modern anticancer treatment research . Pathways in cancer, which describes important signaling pathways such as Wnt signaling and T‐cell receptor signaling, is also an important factor in the progression of NSCLC and development of squamous cell carcinoma of the lung …”

“…51,52 Moreover, it has been found that mutations in cell cycle genes can affect the differentiation of squamous cells in the course of modern anticancer treatment research. 53,54 Pathways in cancer, which describes important signaling pathways such as Wnt signaling and T-cell receptor signaling, is also an important factor in the progression of NSCLC and development of squamous cell carcinoma of the lung. 55,56 To further validate and screen the target genes, we performed a topological analysis in the PPI network.…”

Lung cancer in patients with combined pulmonary fibrosis and emphysema revisited with the 2015 World Health Organization classification of lung tumors

“…This finding was consistent with previous studies. 9,11 As more than half of lung SqCC patients may be candidates for molecularly targeted treatment, 13 the correlation between the histological subtypes and geneexpression data should be further investigated in the future. This finding might suggest therapeutic effect on the survival of patients with lung cancer and CPFE.…”

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

“…34 In the thymus, cancers with basaloid features show a more varied histology (including a wide range of proliferative activities, common macropapillary growth pattern and association with cysts) and a broader spectrum of clinical aggressiveness. 35 Genetic data are sparse and not overlapping with those of pulmonary basaloid squamous cell carcinoma.…”