Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma
Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma
复制标题
DOI：
10.1016/j.jid.2019.03.1163
复制
发表时间：
2019-11-01
影响因子：
6.5
通讯作者：
Sarin, Kavita Y.
中科院分区：
文献类型：
--
作者：
Chiang, Audris;Tan, Caroline Z.;Sarin, Kavita Y.
基底鳞状细胞癌（BSC）是一种侵袭性皮肤肿瘤，具有基底细胞癌（BCC）和鳞状细胞癌（SCC）的特征。虽然BCC和SCC发展的遗传驱动因素已被广泛表征，但BSC尚未得到很好的研究，并且仍然不清楚这些肿瘤最初是否来源于BCC或SCC。此外，尚不清楚哪些分子途径介导肿瘤角质形成细胞向基底细胞样或鳞状细胞表型的重编程。我们试图描述散发性BSC的基因组改变，以阐明这些混合瘤的起源。我们确定了频繁的刺猬（Hh）途径突变的BSC，暗示Hh失调的主要驱动事件BSC。BCC和SCC驱动基因的主成分分析进一步证明了BCC和BSC之间的遗传相似性。此外，45%的BSC在SWI/SNF复合物基因ARID 1A中具有复发性突变，进化分析显示ARID 1A突变发生在PTCH 1之后但在SCC驱动突变之前，表明ARID 1A突变可能赋予可塑性，从而实现鳞状化。最后，我们证明了丝裂原活化蛋白激酶途径的激活和与BSC鳞状化相关的Hh信号的丢失。总的来说，这些结果支持从BCC遗传衍生的BSC和突出参与调节基底细胞和鳞状细胞表型之间的肿瘤重编程的潜在因素。
Basosquamous carcinoma (BSC) is an aggressive skin neoplasm with the features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While genetic drivers of BCC and SCC development have been extensively characterized, BSC has not been well studied, and it remains unclear whether these tumors originally derive from BCC or SCC. In addition, it is unknown which molecular pathways mediate the reprogramming of tumor keratinocytes toward basaloid or squamatized phenotypes. We sought to characterize the genomic alterations underlying sporadic BSC to elucidate the derivation of these mixed tumors. We identifed frequent Hedgehog (Hh) pathway mutations in BSCs, implicating Hh deregulation as the primary driving event in BSC. Principal component analysis of BCC and SCC driver genes further demonstrate the genetic similarity between BCC and BSC. In addition, 45% of the BSCs harbor recurrent mutations in the SWI/SNF complex gene, ARID1A, and evolutionary analysis revealed that ARID1A mutations occur after PTCH1 but before SCC driver mutations, indicating that ARID1A mutations may bestow plasticity enabling squamatization. Finally, we demonstrate mitogen-activated protein kinase pathway activation and the loss of Hh signaling associated with the squamatization of BSCs. Overall, these results support the genetic derivation of BSCs from BCCs and highlight potential factors involved in modulating tumor reprogramming between basaloid and squamatized phenotypes.