Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; Department of Dermatology, The Royal London Hospital, Barts Health NHS Trust, London, United Kingdom.
Centre for Cancer Genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
J Invest Dermatol. 2021 Jul;141(7):1664-1674.e7. doi: 10.1016/j.jid.2020.12.024. Epub 2021 Jan 19.
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.
光化性角化病（AK）是表皮角质形成细胞异型增生的病变，是侵袭性皮肤鳞状细胞癌（cSCC）的前体。由于在这一进展的所有阶段都具有大量的紫外线诱导的突变负担，因此确定驱动从正常皮肤到 AK 皮肤再到侵袭性 cSCC 皮肤的特定基因组改变是具有挑战性的。在本研究中，我们报告了迄今为止最大的 AK 全外显子组测序研究，并对这些病变进行了突变特征和候选驱动基因分析。我们在来自免疫抑制和免疫功能正常的患者的 37 个 AK 中证明，在突变负担、拷贝数改变、突变特征和驱动基因突变模式方面，AK 与 cSCC 具有显著的相似性。我们确定了 44 个显著突变的 AK 驱动基因，并证实这些基因在 cSCC 中也发生了类似的改变。我们在暴露于该药物的所有 AK 患者中均发现了巯嘌呤的突变特征，进一步证明了其在角质形成细胞癌变中的作用。cSCC 与 AK 相比，具有更高水平的样本内异质性。信号通路的改变也不同，cSCC 中免疫相关信号和 TGFβ 信号的突变明显更多。将我们的发现与独立的基因表达数据集相结合，证实失调的 TGFβ 信号可能代表 AK‒cSCC 进展中的一个重要事件。
