Poster Presentation 43rd Lorne Genome Conference 2022

Non-coding somatic drivers in metastases cSCC and associated statistical challenges (#122)

Amarinder Singh Thind 1 2 , Bruce Ashford 1 2 3 , Dario Strbenac 4 , Ruta Gupta 5 , Jonathan Clark 6 , N. Gopalakrishna Iyer 7 , Jenny Mitchell 8 , Jenny Lee 3 , Simon Muller 6 9 , Elahe Minaei 1 2 , Jay Perry 2 , Marie Ranson 1 2
  1. Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
  2. University of Wollongong, Northfields Ave, North Wollongong, NSW, Australia
  3. Department of Medical Oncology, Chris O’Brien Lifehouse, Sydney, NSW, Australia
  4. The University of Sydney, Sydney, NSW, Australia
  5. Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  6. Department of Head and Neck Surgery, Chris O’Brien Lifehouse, Sydney, NSW, Australia
  7. National Cancer Center, Singapore
  8. Illawarra Shoalhaven Local Health District Wollongong, Wollongong, NSW, Australia
  9. Department of Otorhinolaryngology, Head and Neck Surgery, Zurich University Hospital and University of Zurich, Zurich, Switzerland

 Metastatic cutaneous squamous cell carcinoma (cSCC) is associated with a high risk of recurrence and poor prognosis. There is limited published data exploring non-coding cSCC Metastatic genomes. Our study use WGS on matched tumor and blood DNA to detect somatic genetic alterations from 25 patients with regional metastases of head and neck cSCC. Our computational analyses interrogate the clinical impacts of genetic alterations on metastatic cSCC for the coding and non-coding genome. 

 

In the non-coding genome, 3’UTR regions of EVC (48%), PPP1R1A (48%) and LUM (16%) were functionally altered (Q-value < 0.05). Further, significant functional alterations are observed in the tumor suppressing lncRNA LINC01003 ( 68% of specimens, Q-value: 0.0158). High mutation rate at active transcription factor binding sites (TFBS) is postulated to be due to E26 transformation-specific (ETS) TFs induced cyclobutane pyrimidine dimers (CPDs) hotspots or linked to a decreased level of nucleotide excision repair (NER) as seen in another UV-induced cancer, melanoma. This phenomenon leads to many false-positive mutational driver detections from the regulatory regions of promotor/5' UTR regions. We highlight this issue for cSCC cancer from our mutational significance analysis.

 

In addition, significant recurrent copy number loss in tumor suppressor genes KANSL1 and PTPRD and gain in CALR, CCND1 and FGF3 was observed for coding regions. Significantly mutated gene analysis predicted TP53, CDKN2A, ZNF750 as potential drivers of the metastasis cSCC. Indel signature analysis highlight dominance of ID signature 13 followed by ID8 & ID9. Interestingly, ID 9 has previously been shown to have no association with skin melanoma (high tumour mutational burden like cSCC), unlike ID 13 and 8, suggesting some point of difference between these two skin-based diseases. 

 

This study proposes potential non-coding drivers for metastasis cSCC and highlights existing statistical challenges that need to be resolved for cancers with high mutational burdens. 

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