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Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma Audris Chiang1,2,7, Caroline Z

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Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma Audris Chiang1,2,7, Caroline Z See related commentary on pg 2258 ORIGINAL ARTICLE Genetic Mutations Underlying Phenotypic Plasticity in Basosquamous Carcinoma Audris Chiang1,2,7, Caroline Z. Tan1,7, Franc¸ois Kuonen1, Luqman M. Hodgkinson1, Felicia Chiang3, Raymond J. Cho4, Andrew P. South5,JeanY.Tang1, Anne Lynn S. Chang1, Kerri E. Rieger1,6, Anthony E. Oro1 and Kavita Y. Sarin1 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 orig- inally derive from BCC or SCC. In addition, it is unknown which molecular pathways mediate the reprog- ramming 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. Journal of Investigative Dermatology (2019) 139, 2263e2271; doi:10.1016/j.jid.2019.03.1163 INTRODUCTION metatypical carcinoma, and BCC with squamous differenti- Basosquamous carcinoma (BSC) is a clinically aggressive ation (Allen et al., 2014; Costantino et al., 2006; De Stefano neoplasm of the skin with the features of both basal cell et al., 2012; Garcia et al., 2009) and represents the pheno- carcinoma (BCC) and squamous cell carcinoma (SCC). BSC typic plasticity that can occur between BCC and SCC. represents 1.2e2.7% of all skin carcinomas and displays an Despite recognition of the intermediate histopathologic fea- aggressive local growth pattern with high potential for tures of BSC (Figure 1), it remains unclear whether these tu- recurrence and metastases, with a prevalence rate up to 7.4% mors are initially derived from BCC or SCC, and the genetic for distant metastases, higher than that of SCC and BCC mutations underlying the development of BSC have not been (Garcia et al., 2009; Volkenstein et al., 2010). While the explored. molecular nature of BSC is unclear, most tumors contain In contrast to BSC, the genetics of BCC and SCC are well areas of both BCC and SCC with a transitional zone of in- described. Uncontrolled activation of the Hedgehog (Hh) termediate differentiation (Maloney, 2000). This entity pathway drives the development of BCCs. Loss of the tumor has been referred to as basosquamous cell carcinoma, suppressor PTCH1 and gain of function of the G proteinecoupled receptor Smoothened (SMO) are the most common mutations that inappropriately activate the Hh 1Department of Dermatology, Stanford University School of Medicine, pathway (Atwood et al., 2015; Sharpe et al., 2015). Other Stanford, California, USA; 2University of California, Irvine School of Medicine, Irvine, California, USA; 3Department of Civil and Environmental genetic drivers of BCC identified through exome sequencing Engineering, University of California, Irvine, Irvine, California, USA; studies include PTEN, MYCN, PPP6C, GRIN2A, GLI1, 4Department of Dermatology, University of California, San Francisco, San CSMD3, DCC, PREX2, and APC (Bonilla et al., 2016; 5 Francisco, California, USA; Department of Dermatology and Cutaneous Jayaraman et al., 2014). In contrast to BCC, SCC contains Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; and 6Department of Pathology, Stanford University School of Medicine, greater genetic heterogeneity. Commonly mutated genes in Stanford, California, USA SCC include activating mutations in HRAS and disruptions of 7These authors contributed equally to this work. the TGFBR1, TGFBR2, NOTCH1, and NOTCH2 genes Correspondence: Kavita Sarin, Department of Dermatology, 450 Broadway (Cammareri et al., 2016; Rose et al., 2017; South et al., Street, Pavilion C, 2nd Floor e MC5334, Redwood City, California 94063. 2014). Genetic studies have also reported additional muta- E-mail: [email protected] tions in CASP8, CDKN2A, NOTCH3, KRAS, NRAS, PDK1, Abbreviations: BCC, basal cell carcinoma; BSC, basosquamous carcinoma; BAP1, AJUBA, KMT2D, MYH9, TRAF3, NSD1, CDH1, and Hh, Hedgehog; MAPK, mitogen-activated protein kinase; SCC, squamous cell TP63 (Pickering et al., 2014; Schwaederle et al., 2015; carcinoma. Yilmaz et al., 2017). Received 1 September 2018; revised 2 March 2019; accepted 19 March 2019; accepted manuscript published online 15 June 2019; corrected proof Several recent studies have demonstrated the squamatiza- published online 16 August 2019 tion of BCCs with SMO inhibitor vismodegib (Ransohoff ª 2019 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. www.jidonline.org 2263 A Chiang et al. Genetics Drivers of Basosquamous Carcinoma Table 1. Comparison of BCC and SCC Driver Gene Mutation Frequencies BSC BCC SCC Sample Sample Sample BCC SCC Mutation Mutation Mutation versus versus Frequency Frequency Frequency BSC P- BSC P- Gene (N [ 20) (N [ 16) (N [ 52) Value1 value1 BCC Drivers PTCH1 0.45 0.44 0.10 0.95 0.001 SMO2 0.05 0.25 0.00 0.08 0.10 MYCN3 0.15 0.19 0.06 0.75 0.20 PPP6C3 0.05 0.25 0.00 0.08 0.10 GRIN2A 0.35 0.50 0.27 0.36 0.50 CSMD3 0.60 0.56 0.75 0.82 0.21 DCC 0.10 0.25 0.31 0.23 0.07 PREX2 0.05 0.38 0.19 0.01 0.13 APC 0.10 0.19 0.27 0.45 0.12 Figure 1. Histopathology of BSC. Histopathology demonstrates a tumor with PTEN 0.05 0.06 0.00 0.87 0.10 basaloid areas containing tumor cells with scant cytoplasm arranged in cords PIK3CA3 0.10 0.13 0.04 0.78 0.31 with peripheral palisading, retraction artifact, and mucinous stroma, SCC Drivers transitioning into areas composed of squamous cells containing abundant CDKN2A 0.00 0.00 0.15 N/A 0.02 eosinophilic cytoplasm (original magnification Â20). Transition zones NOTCH1 0.15 0.31 0.46 0.24 0.01 between the basaloid areas (in the bottom portion of the image) and NOTCH2 0.20 0.25 0.37 0.72 0.18 squamous areas (in the upper left portion of the image) are marked with NOTCH3 0.15 0.06 0.19 0.39 0.68 asterisks (*). Bar ¼ 50 mm. BSC, basosquamous carcinoma. KRAS3 0.00 0.00 0.02 N/A 0.53 NRAS3 0.00 0.00 0.02 N/A 0.53 et al., 2015; Zhao et al., 2015; Zhu et al., 2014). These re- HRAS3 0.00 0.00 0.12 N/A 0.11 ports describe cases of SCC arising in areas of the original RASA1 0.00 0.00 0.06 N/A 0.26 BCC tumor bed, within tumors that have stopped responding TGFBR1 0.15 0.13 0.06 0.86 0.20 clinically to vismodegib or contained areas responding TGFBR2 0.10 0.06 0.08 0.66 0.75 differentially to treatment, suggesting that the process of the CEBPA 0.05 0.00 0.00 0.36 0.10 dedifferentiation of BCC into SCC may enable the BCCs to PDK1 0.05 0.00 0.08 0.36 0.69 evade drug inhibition (Iarrobino et al., 2013; Orouji et al., BAP1 0.10 0.00 0.04 0.19 0.31 2014; Saintes et al., 2015; Zhu et al., 2014). However, it CREBBP 0.25 0.13 0.19 0.37 0.59 BCC and SCC Drivers remains unclear whether these cases of SCC arose indepen- TP53 0.55 0.31 0.58 0.15 0.84 dently or resulted from squamatization of the original BCC. KMT2D/MLL2 0.40 0.44 0.58 0.82 0.18 Recently, Ransohoff et al. (2015) described one case of a AJUBA 0.10 0.13 0.13 0.81 0.69 recurrent SCC-like tumor in the lymph node following the MYH9 0.25 0.38 0.13 0.42 0.24 vismodegib treatment of metastatic BCC. Genetic sequencing TRAF3 0.10 0.13 0.06 0.81 0.53 of the original tumor and recurrent lymph node SCC identi- NSD1 0.20 0.13 0.08 0.55 0.14 fied a common PTCH1 mutation, suggesting that the SCC CDH1 0.05 0.13 0.10 0.42 0.53 most likely arose from the original BCC and that selective CASP8 0.15 0.06 0.19 0.41 0.69 pressure owing to treatment with vismodegib may have been RAC13 0.05 0.00 0.04 0.36 0.85 responsible for this squamatization. However, no studies of ARID1A 0.45 0.19 0.19 0.10 0.03 the derivation of sporadic BSC have been performed to date. TP63 0.05 0.25 0.10 0.08 0.53 Further understanding of the genetics of sporadic BSC may Abbreviations: BCC, basal cell carcinoma; BSC, basosquamous help to elucidate the mechanisms of phenotypic plasticity carcinoma; N/A, not applicable; SCC, squamous cell carcinoma. 1 that enable BCC and SCC to change fate, promote tumor Two-proportion Z-test, P-value two-tailed. 2Includes only known activating SMO mutations. progression, and enable tumors to evade therapy.
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