Whole genome analysis reveals the genomic complexity in metastatic cutaneous squamous cell carcinoma

Abstract

Metastatic cutaneous squamous cell carcinoma (CSCC) is a highly morbid disease requiring radical surgery and adjuvant therapy, which is associated with a poor prognosis. Yet, compared to other advanced malignancies, relatively little is known of the genomic landscape of metastatic CSCC. We have previously reported the mutational signatures and mutational patterns of CCCTC-binding factor (CTCF) regions in metastatic CSCC. However, many other genomic components (indel signatures, non-coding drivers, and structural variants) of metastatic CSCC have not been reported. To this end, we performed whole genome sequencing on lymph node metastases and blood DNA from 25 CSCC patients with regional metastases of the head and neck. We designed a multifaceted computational analysis at the whole genome level to provide a more comprehensive perspective of the genomic landscape of metastatic CSCC. In the non-coding genome, 3′ untranslated region (3′UTR) regions of EVC (48% of specimens), PPP1R1A (48% of specimens), and ABCA4 (20% of specimens) along with the tumor-suppressing long non-coding RNA (lncRNA) LINC01003 (64% of specimens) were significantly functionally altered (Q-value < 0.05) and represent potential non-coding biomarkers of CSCC. Recurrent copy number loss in the tumor suppressor gene PTPRD was observed. Gene amplification was much less frequent, and few genes were recurrently amplified. Single nucleotide variants driver analyses from three tools confirmed TP53 and CDKN2A as recurrently mutated genes but also identified C9 as a potential novel driver in this disease. Furthermore, indel signature analysis highlighted the dominance of ID signature 13 (ID13) followed by ID8 and ID9. ID9 has previously been shown to have no association with skin melanoma, unlike ID13 and ID8, suggesting a novel pattern of indel variation in metastatic CSCC. The enrichment analysis of various genetically altered candidates shows enrichment of “TGF-beta regulation of extracellular matrix” and “cell cycle G1 to S check points.” These enriched terms are associated with genetic instability, cell proliferation, and migration as mechanisms of genomic drivers of metastatic CSCC.

Molecular Alterations in Cutaneous Squamous Cell Carcinoma in Immunocompetent and Immunosuppressed Hosts—A Systematic Review

“…The absence of HOXA9 positively regulates HIF-1 and its downstream glycolytic regulators, which enhances glycolysis necessary for cSCC development, proliferation, migration, and invasion [ 15 ]. Using whole-genome sequencing, Thind et al demonstrated significant recurrent copy number loss in the tumor suppressor genes KANSL1 and PTPRD [ 16 ]. Likewise, KMT2C , CREBBP , and NCOA2 were identified to demonstrate tumor-suppressive roles in the initiation and progression of human cSCC [ 17 ].…”

“…Thind et al also observed that the 3′ UTR regions of EVC (48%), PPP1R1A (48%), and LUM (16%) were significantly functionally altered (Q-value < 0.05) in the non-coding genome of cSCC. Moreover, significant recurrent copy number gains in CALR , CCND1 , and FGF3 were observed for coding regions [ 16 ]. In a recent study by Yan et al, differential expression analysis demonstrated that many members belonging to the S100 gene family, the SPRR gene family, and FABP5 were significantly upregulated in cSCC cells.…”

“…Other research showed that lncRNA TINCR overexpression promoted ALA-PDT-induced apoptosis and autophagy through the ERK1/2-SP3 pathway [ 51 ]. Finally, significant functional alterations were observed in the tumor-suppressing lncRNA LINC01003 (68% of specimens, Q-value: 0.0158) in a recent study analyzing cSCC samples from patients with regional metastases of the head and neck [ 16 ].…”

Sex Disparity for Patients with Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Systematic Review

“…Cancer rates in organ transplant recipients are generally higher, and this rate is between 60–100 times greater than the age-matched population for cSCC. The extremely high tumour mutational burden seen in whole genomic analysis of metastatic cSCC [ 101 ] underpins the predilection for disease progression in those patients with impaired immune surveillance.…”

Evolution of Head and Neck Cutaneous Squamous Cell Carcinoma Nodal Staging—An Australian Perspective

“…HNcSCC is biologically distinct from mucosal HN SCC, with different aetiological factors, demographics, and genetics. Metastatic HNcSCC is the most highly mutated human cancer due to life-long exposure to ultraviolet (UV) radiation, with tumour mutation burdens several folds higher than HN mucosal SCC [ 45 , 46 , 47 , 48 ]. Furthermore, regional metastases from HNcSCC are usually metachronous from the primary tumour and in many cases (20–30%), the primary or index lesion cannot be identified.…”