Upper Aerodigestive Tract Squamous Cell Carcinomas Show Distinct Overall DNA Methylation Profiles and Different Molecular Mechanisms behind WNT Signaling Disruption

Abstract

Upper aerodigestive tract (UADT) tumors present different biological behavior and prognosis, suggesting specific molecular mechanisms underlying their development. However, they are rarely considered as single entities (particularly head and neck subsites) and share the most common genetic alterations. Therefore, there is a need for a better understanding of the global DNA methylation differences among UADT tumors. We performed a genome-wide DNA methylation analysis of esophageal (ESCC), laryngeal (LSCC), oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas, and their non-tumor counterparts. The unsupervised analysis showed that non-tumor tissues present markedly distinct DNA methylation profiles, while tumors are highly heterogeneous. Hypomethylation was more frequent in LSCC and OPSCC, while ESCC and OSCC presented mostly hypermethylation, with the latter showing a CpG island overrepresentation. Differentially methylated regions affected genes in 127 signaling pathways, with only 3.1% of these being common among different tumor subsites, but with different genes affected. The WNT signaling pathway, known to be dysregulated in different epithelial tumors, is a frequent hit for DNA methylation and gene expression alterations in ESCC and OPSCC, but mostly for genetic alterations in LSCC and OSCC. UADT tumor subsites present differences in genome-wide methylation regarding their profile, intensity, genomic regions and signaling pathways affected.

FBXL7 Body Hypomethylation Is Frequent in Tumors from the Digestive and Respiratory Tracts and Is Associated with Risk-Factor Exposure

“…Methylome analysis was performed as previously described [ 19 ]. Briefly, DNA was extracted from ESCC and HNSCC tumors and their respective non-tumor adjacent tissues (NTST), all snap-frozen, with the DNeasy Blood & Tissue Kit (Qiagen, Hilden, Germany), as follows: 16 NTST and 24 ESCC; 12 NTST and 20 LSCC; seven NTST and 15 OCSCC; and 8 OPSCC.…”

“…Tumors from the upper aerodigestive tract (UAT) show few recurrently mutated genes, suggesting that other molecular mechanisms take part in their development. In these tumors, DNA methylation is intricately linked with risk-factor exposure [ 18 ] and malignant transformation [ 19 ]. The esophagus (ESCC) and, among the head and neck organs, the oral cavity (OCSCC), larynx (LSCC) and oropharynx (OPSCC) are most commonly affected by squamous cell carcinomas [ 20 , 21 ].…”

Head and Neck Cancers Are Not Alike When Tarred with the Same Brush: An Epigenetic Perspective from the Cancerization Field to Prognosis

“…In comparison to the few common genetic alterations found in HNSCC generally, DNA methylation shows more frequent and subsite-specific changes, an important asset for molecular diagnosis [24,212,213,234]. P16INK4A is hypermethylated in 27-44% of HNSCC [93,97,98,235]; however, it has already been reported that almost half of the samples could not be analyzed due to loss of heterozygosity [98,236].…”

“…Although differences according to tumor site and associated risk factors exist, these only partially explain this heterogeneity. In this context, epigenetic alterations have gained attention due to their frequency and site-specific pattern [23][24][25][26], being promising biomarkers. In the following sections, we bring together the current knowledge on alterations of DNA methylation and microRNA expression in HNSCC natural history, focusing on how they contribute to each step of the process and on their applicability as biomarkers of exposure, HNSCC development, progression, and response to therapy.…”

Hypermethylation-Mediated lncRNA MAGI2-AS3 Downregulation Facilitates Malignant Progression of Laryngeal Squamous Cell Carcinoma via Interacting With SPT6

“…Existing research has suggested that epigenetics takes on a critical significance to LSCC development and progression 10 . DNA methylation refers to one of the most characteristic epigenetic modifications, and it is capable of regulating gene transcription.…”