The Genomic Landscape of Actinic Keratosis

Journal article


Thomson, J., Bewicke-Copley, F., Anene, C., Gulati, A., Nagano, A., Purdie, K., Inman, G.J., Proby, C.M., Leigh, I.M., Harwood, C.A. and Wang, J. (2021). The Genomic Landscape of Actinic Keratosis. The Journal of Investigative Dermatology. https://doi.org/10.1016/j.jid.2020.12.024
AuthorsThomson, J., Bewicke-Copley, F., Anene, C., Gulati, A., Nagano, A., Purdie, K., Inman, G.J., Proby, C.M., Leigh, I.M., Harwood, C.A. and Wang, J.
Abstract

Actinic keratoses (AKs) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression from normal skin to skin with AK to skin with invasive cSCC is challenging because of the massive UVR-induced mutational burden characteristic at all stages of this progression. In this study, we report the largest AK whole-exome sequencing study to date and perform a mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AKs from both immunosuppressed and immunocompetent patients that there are significant similarities between AKs and cSCC in terms of mutational burden, copy number alterations, mutational signatures, and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in cSCC. We identify azathioprine mutational signature in all AKs from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. cSCCs differ from AKs in having higher levels of intrasample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGFβ signaling significantly more mutated in cSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGFβ signaling may represent an important event in AK‒cSCC progression.

Year2021
JournalThe Journal of Investigative Dermatology
PublisherElsevier
ISSN1523-1747
Digital Object Identifier (DOI)https://doi.org/10.1016/j.jid.2020.12.024
Web address (URL)https://www.jidonline.org/article/S0022-202X(21)00014-2/fulltext
Publication dates
Print21 Jun 2021
Online19 Jan 2021
Publication process dates
Accepted16 Dec 2020
Deposited23 Jun 2022
Accepted author manuscript
License
File Access Level
Open
Permalink -

https://openresearch.lsbu.ac.uk/item/8zyq2

  • 69
    total views
  • 41
    total downloads
  • 3
    views this month
  • 0
    downloads this month

Export as

Related outputs

Cumulative incidence and risk factors for cutaneous squamous-cell carcinoma metastases in organ transplant recipients: the SCOPE-ITSCC metastases study, a prospective multi-center study.
de Jong, E., Genders, R., Harwood, C.A, Green, A.C., Plasmeijer, E.I., Proby, C., Geissler, E., Ferrándiz-Pulido, C., Ducroux, E., Euvrard, S., Geusau, A., Jahn-Bassler, K., Borik-Heil, L., Rácz, E., Nägeli, M., Hofbauer, G.F., Piaserico, S., Russo, I., Mackintosh, L., Borges-Costa, J., Angeliki-Gkini, M., Zavattaro, E., Savoia, P., Imko-Walszuk, B., Dębska-Slizień, A., Garmyn, M., van Kelst, S., Ricar, J., Cetkovska, P., Matin, R., Güleç, A.T., Seçkin, D., Anene, C.A., Oliveira, W.R.P., Rademaker, M., Goeman, J., van Geloven, N., Ruiz, E., Murad, F., Karn, E., Schmults, C.D. and Bouwes Bavinck, J.N. (2024). Cumulative incidence and risk factors for cutaneous squamous-cell carcinoma metastases in organ transplant recipients: the SCOPE-ITSCC metastases study, a prospective multi-center study. Journal of the American Academy of Dermatology. https://doi.org/10.1016/j.jaad.2024.01.040
Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multi-gene prognostic signature associated with metastasis.
Wang J, Harwood CA, Bailey E, Bewicke-Copley F, Anene, C., Thomson J, Qamar MJ, Laban R, Nourse C, Schoenherr C, Treanor-Taylor M, Healy E, Lai C, Craig P, Moyes C, Rickaby W, Martin J, Proby C, Inman GJ and Leigh IM (2023). Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multi-gene prognostic signature associated with metastasis. Journal of the American Academy of Dermatology. 89 (6), pp. 1159-1166. https://doi.org/10.1016/j.jaad.2023.08.012
Decosus: An R Framework for Universal Integration of Cell Proportion Estimation Methods.
Anene, C.A., Taggart, E., Harwood, C., Pennington, D.J. and Wang, J. (2022). Decosus: An R Framework for Universal Integration of Cell Proportion Estimation Methods. Frontiers in genetics. 13, p. 802838. https://doi.org/10.3389/fgene.2022.802838
Dysregulation of the miR-30c/DLL4 axis by circHIPK3 is essential for KSHV lytic replication
Harper, K.L., Mottram, T.J., Anene, C., Foster, B., Patterson, M.R., McDonnell, E., Macdonald, A., Westhead, D. and Whitehouse, A. (2022). Dysregulation of the miR-30c/DLL4 axis by circHIPK3 is essential for KSHV lytic replication. EMBO Reports. (e54117). https://doi.org/10.15252/embr.202154117
ACSNI: An unsupervised machine-learning tool for prediction of tissue-specific pathway components using gene expression profiles
Anene, C., Khan F., Bewicke-Copley, F., Maniati, E. and Wang, J. (2021). ACSNI: An unsupervised machine-learning tool for prediction of tissue-specific pathway components using gene expression profiles. Patterns. 2 (6), p. 100270. https://doi.org/10.1016/j.patter.2021.100270
SFPQ promotes an oncogenic transcriptomic state in melanoma
Bi, O., Anene, C., Nsengimana, J., Roberts, W., Newton-Bishop, J. and Boyne, J.R. (2021). SFPQ promotes an oncogenic transcriptomic state in melanoma. Oncogene. 40, pp. 5192-5203. https://doi.org/10.1038/s41388-021-01912-4
Systematic Evaluation of Somatic Cis-Regulatory Mutations in Follicular Lymphoma
Firat U., Bewicke-Copley, F., Anene, C., Schlesner, M., Icgc MMML-Seq Project3, Siebert, R., Okosun, J., Fitzgibbon, J. and Wang, J (2020). Systematic Evaluation of Somatic Cis-Regulatory Mutations in Follicular Lymphoma. American Society of Hematology. https://doi.org/10.1182/blood-2020-142623
The role of CAF derived exosomal microRNAs in the tumour microenvironment of melanoma
Shelton, M., Anene, C., Nsengimana, J., Roberts, W., Newton-Bishop, J. and Boyne, J.R. (2020). The role of CAF derived exosomal microRNAs in the tumour microenvironment of melanoma. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1875 (1), p. 188456. https://doi.org/10.1016/j.bbcan.2020.188456
Merkel cell polyomavirus small tumour antigen activates the p38 MAPK pathway to enhance cellular motility
Dobson, S.J., Anene, C., Boyne, J.R., Mankouri, J., Macdonald, A. and Whitehouse, A (2020). Merkel cell polyomavirus small tumour antigen activates the p38 MAPK pathway to enhance cellular motility. Biochemical Journal. 477 (14), pp. 2721-2733. https://doi.org/10.1042/BCJ20200399
Platelet microparticle delivered microRNA-Let-7a promotes the angiogenic switch
Anene, C., Graham, A.M., Boyne, J. and Roberts, W. (2018). Platelet microparticle delivered microRNA-Let-7a promotes the angiogenic switch. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. https://doi.org/10.1016/j.bbadis.2018.04.013
Platelet induced hepatocellular carcinoma HEPG2 cell proliferation and angiogenic potential is integrin IIb3 dependent.
Rashed, Al-Hammad, Anene, C., Graham, A.M. and Roberts, W. (2015). Platelet induced hepatocellular carcinoma HEPG2 cell proliferation and angiogenic potential is integrin IIb3 dependent. Taylor & Francis. https://doi.org/10.3109/09537104.2015.1115703