Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA; University of California, Irvine School of Medicine, Irvine, California, USA.
Department of Dermatology, Stanford University School of Medicine, Stanford, California, USA.
J Invest Dermatol. 2019 Nov;139(11):2263-2271.e5. doi: 10.1016/j.jid.2019.03.1163. Epub 2019 Jun 15.
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.
基底鳞状细胞癌 (BSC) 是一种具有基底细胞癌 (BCC) 和鳞状细胞癌 (SCC) 特征的侵袭性皮肤肿瘤。虽然 BCC 和 SCC 发展的遗传驱动因素已被广泛研究，但 BSC 研究甚少，尚不清楚这些肿瘤最初是源自 BCC 还是 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样或鳞状表型的重编程。我们试图描述散发性 BSC 的基因组改变，以阐明这些混合肿瘤的起源。我们发现 BSCs 中存在频繁的 Hedgehog (Hh) 通路突变，提示 Hh 失调是 BSC 的主要驱动事件。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 BSCs 中存在 SWI/SNF 复合物基因 ARID1A 的复发性突变，进化分析表明 ARID1A 突变发生在 PTCH1 之后但在 SCC 驱动突变之前，表明 ARID1A 突变可能赋予了可塑性，从而实现鳞状分化。最后，我们证明了 BSCs 鳞状分化时丝裂原活化蛋白激酶通路的激活和 Hh 信号的丢失。总之，这些结果支持 BSC 源自 BCC 的遗传起源，并强调了在调节基底样和鳞状表型之间肿瘤重编程方面的潜在因素。
