Distinct signatures of lung cancer types: aberrant mucin O-glycosylation and compromised immune response

Abstract

Background: Genomic initiatives such as The Cancer Genome Atlas (TCGA) contain data from-omics profiling of thousands of tumor samples, which may be used to decipher cancer signaling, and related alterations. Managing and analyzing data from large-scale projects, such as TCGA, is a demanding task. It is difficult to dissect the high complexity hidden in genomic data and to account for inter-tumor heterogeneity adequately. Methods: In this study, we used a robust statistical framework along with the integration of diverse bioinformatic tools to analyze next-generation sequencing data from more than 1000 patients from two different lung cancer subtypes, i.e., the lung adenocarcinoma (LUAD) and the squamous cell carcinoma (LUSC). Results: We used the gene expression data to identify co-expression modules and differentially expressed genes to discriminate between LUAD and LUSC. We identified a group of genes which could act as specific oncogenes or tumor suppressor genes in one of the two lung cancer types, along with two dual role genes. Our results have been validated against other transcriptomics data of lung cancer patients. Conclusions: Our integrative approach allowed us to identify two key features: a substantial up-regulation of genes involved in O-glycosylation of mucins in LUAD, and a compromised immune response in LUSC. The immune-profile associated with LUSC might be linked to the activation of three oncogenic pathways, which promote the evasion of the antitumor immune response. Collectively, our results provide new future directions for the design of target therapies in lung cancer.

Identification of lncRNA Signature Associated With Pan-Cancer Prognosis

“…BRCA, UCEC, and SKCM patients have a much higher five-year survival rate (>90%, 90%, and 92% respectively) compared to HNSC (50%). Besides, we found patients with LUSC and LUAD, which unlike BRCA, UCEC, SKCM, and HNSC, etc., are not densely mapped to any specific lncRNA phenotypes, which indicates the prognoses of LUSC and LUAD patients are more heterogeneous, this finding is supported by recent research studies [40,41]. The prognostic value gradually declined with the phenotype arrangements approaching the center of the diagram.…”

TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival

“…This questions whether wt TP53 LUSC has distinct etiology and should be considered as an atypical LUSC subtype? On this point it is noteworthy that four of the cases considered atypical in a previous study ([ 34 ] and references within) were among this group.…”

“…Specifically, the calculated Pearson coefficient value close to 1 indicates a significant positive linear correlation, using the Spearman’s test of significance. We considered that rather than low tumor purity/high tumor infiltrate being a ‘problem’ (as in other studies which discard samples of low purity, e.g., [ 34 ]), we postulated that the nature and quantity of immune infiltrate may be prognostic in female and male LUAD patients.…”

“…Specifically, the calculated Pearson coefficient value close to 1 indicates a significant positive linear correlation, using the Spearman's test of significance. We considered that rather than low tumor purity/high tumor infiltrate being a 'problem' (as in other studies which discard samples of low purity, e.g., [34]), we postulated that the nature and quantity of immune infiltrate may be prognostic in female and male LUAD patients. As longevity is more prolonged for females than males with LUAD ( Figure 1A) and this is most evident for female wt TP53 cases ( Figure 1D,E), we examined the proportion of immune infiltrate across the sexes according to TP53 status (wt or mutant).…”

Lung squamous cell carcinoma and lung adenocarcinoma differential gene expression regulation through pathways of Notch, Hedgehog, Wnt, and ErbB signalling

“…Another group reported differential and clinically important subtypes of LUSC based on gene expression profiles 20 . Finally, a recent comparison of LUSC and LUAD showed distinct expression profiles of genes involved in tumour immune response 21,22 . Alternations of Notch, Hh, Wnt and ErbB pathways were repeatedly associated with development and progression of many malignancies.…”