Oral Presentation Skin Cancer 2024

Colocalisation of germline genetic risk for skin cancer with long non-coding RNAs (#103)

Matthew H Law 1 2 3 , Isela Sarah Rivera 3 4 5 , Mathias Seviiri 1 2 3 , Jonathan Beesley 6 , Lambros T Koufariotis 7 , Nic Waddell 7 8 , Maria Teresa Landi 9 , Mark M Iles 10 11 , Kevin M Brown 9 , Juliet French 4 , Stacey Edwards 5
  1. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
  2. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  3. School of Biomedical Sciences, The University of Queensland, Brisbane, Brisbane, QLD, Australia
  4. Functional Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  5. Functional Cancer Genomics, QIMR Berghofer Medical Research Institute, Queensland, QLD, Australia
  6. Genome Variation and Regulation in Disease, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  7. Medical Genomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  8. Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
  9. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  10. Leeds Institute for Data Analytics, University of Leeds, Leeds, United Kingdom
  11. NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

The three major skin cancers, cutaneous melanoma, basal cell carcinoma and squamous cell carcinoma, overlap in their risk factors. A large number of shared and disease-specific germline risk loci have been identified for these cancers 1–3. Identifying specific risk genes at these loci is more advanced for melanoma than the other two cancers 4–7, and for many loci, the underlying gene is yet to be determined.

In addition to protein-coding genes, noncoding RNAs can also impact disease risk. Long noncoding RNAs (lncRNAs) have previously been found to be important in skin cancer  8–10. Germline genetic variants that influence skin cancer risk may do so by regulating the expression of  lncRNAs. However, lncRNAs can be expressed at very low levels in a cell-specific manner, and as a result, are often not annotated during RNA sequencing.

To address this limitation, we have previously mapped novel lncRNAs in melanocytes, fibroblasts and keratinocytes and measured their levels in 106 primary melanocyte cultures with genome-wide genotyping. After correcting for multiple testing this identified 646 lncRNAs with a genetic variant associated with their expression. Across the three skin cancers, 21 germline risk loci colocalised with these lncRNA expression signals, including one on  chromosome 15 containing the OCA2 gene. To improve our power to detect lncRNAs important for skin cancer we will report on extending this analysis from primary melanocytes to melanoma tumour data.

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