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

Amarinder Singh Thind; Bruce Ashford; Dario Strbenac; Jenny Mitchell; Jenny Lee; Simon A Mueller; Elahe Minaei; Jay R Perry; Sydney Ch'ng; N Gopalakrishna Iyer; Jonathan R Clark; Ruta Gupta; Marie Ranson

doi:10.3389/fonc.2022.919118

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

Front Oncol. 2022 Aug 2:12:919118. doi: 10.3389/fonc.2022.919118. eCollection 2022.

Authors

Amarinder Singh Thind^{1

2}, Bruce Ashford^{1

2

3}, Dario Strbenac⁴, Jenny Mitchell³, Jenny Lee^{5

6}, Simon A Mueller^{5

7}, Elahe Minaei^{2

8}, Jay R Perry^{2

8}, Sydney Ch'ng^{4

5}, N Gopalakrishna Iyer^{9

10}, Jonathan R Clark^{4

5

11}, Ruta Gupta¹², Marie Ranson^{2

8}

Affiliations

¹ School of Medicine, University of Wollongong, Wollongong, NSW, Australia.
² Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
³ Illawarra Shoalhaven Local Health District, Wollongong, NSW, Australia.
⁴ Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, NSW, Australia.
⁵ Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
⁶ Department of Clinical Medicine, Macquarie University, Sydney, NSW, Australia.
⁷ Department of Otorhinolaryngology, Head and Neck Surgery, Zurich University Hospital and University of Zurich, Zurich, Switzerland.
⁸ School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia.
⁹ Department of Head and Neck Surgery, National Cancer Center, Singapore, Singapore.
¹⁰ Duke-NUS Medical School, Singapore, Singapore.
¹¹ Royal Prince Alfred Institute of Academic Surgery, Sydney Local Health District, Sydney, NSW, Australia.
¹² Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

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.

Keywords: CSCC; UTR - Untranslated regions; cutaneous; metastases; mutations; noncoding; squamous cell carcinoma; whole genome sequencing.