Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy


Veeramachaneni, Ratna, Walker, Thomas, Revil, Timothee, De Weck, Antoine, Badescu, Dunarel, O'Sullivan, James, Higgins, Catherine, Elliott, Louise, Liloglou, Triantafillos ORCID: 0000-0003-0460-1404, Risk, Janet M ORCID: 0000-0002-8770-7783 et al (show 10 more authors) (2019) Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy. SCIENTIFIC REPORTS, 9 (1). 11992-.

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Abstract

We report changes in the genomic landscape in the development of head and neck squamous cell carcinomas HNSCC from potentially premalignant lesions (PPOLS) to malignancy and lymph node metastases. Likely pathological mutations predominantly involved a relatively small set of genes reported previously (TP53, KMT2D, CDKN2A, PIK3CA, NOTCH1 and FAT1) but also other predicted cancer drivers (MGA, PABPC3, NR4A2, NCOR1 and MACF1). Notably, all these mutations arise early and are present in PPOLs. The most frequent genetic changes, which follow acquisition of immortality and loss of senescence, are of consistent somatic copy number alterations (SCNAs) involving chromosomal regions enriched for genes in known and previously unreported cancer-related pathways. We mapped the evolution of SCNAs in HNSCC progression. One of the earliest SCNAs involved deletions of CSMD1 (8p23.2). CSMD1 deletions or promoter hypermethylation were present in all of the immortal PPOLs and occurred at high frequency in the immortal HNSCC cell lines. Modulation of CSMD1 in cell lines revealed significant suppression of proliferation and invasion by forced expression, and significant stimulation of invasion by knockdown of expression. Known cancer drivers NOTCH1, PPP6C, RAC1, EIF4G1, PIK3CA showed significant increase in frequency of SCNA in transition from PPOLs to HNSCC that correlated with their expression. In the later stages of progression, HNSCC with and without nodal metastases showed some clear differences including high copy number gains of CCND1, hsa-miR-548k and TP63 in the metastases group.

Item Type: Article
Uncontrolled Keywords: Keratinocytes, Humans, Head and Neck Neoplasms, Cell Transformation, Neoplastic, Disease Progression, Disease Susceptibility, Genomic Instability, Neoplasm Staging, Chromosome Mapping, Gene Expression Profiling, Computational Biology, Mutation, DNA Copy Number Variations, Biomarkers, Cellular Senescence, Squamous Cell Carcinoma of Head and Neck
Depositing User: Symplectic Admin
Date Deposited: 06 Aug 2019 10:36
Last Modified: 19 Jan 2023 00:36
DOI: 10.1038/s41598-019-48229-7
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3051055
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