Genomic analysis of metastatic cutaneous squamous cell carcinoma.
Genomic analysis of metastatic cutaneous squamous cell carcinoma.
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DOI：
10.1158/1078-0432.ccr-14-1773
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发表时间：
2015-03-15
期刊：
影响因子：
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通讯作者：
Hammerman PS
中科院分区：
文献类型：
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作者：
Li YY;Hanna GJ;Laga AC;Haddad RI;Lorch JH;Hammerman PS
罕见的5%的皮肤鳞状细胞癌转移，缺乏FDA批准的治疗方法，预后不良。我们的目的是确定在这个很少研究的转移性cSCC群体中的复发性基因组改变。我们对29例cSCC患者淋巴结转移的504个癌症相关基因进行了靶向测序，并确定了与转移性cSCC相关的突变和体细胞拷贝数改变。我们确定了显著突变、缺失和扩增的基因，以及与临床变量相关的基因组改变。cSCC基因组是异质的，具有广泛变化的基因组改变数量，并且似乎与HPV无关。我们发现了以前鉴定的复发性改变的基因（TP 53，CDKN 2A，NOTCH 1/2），但也有广泛的致癌突变影响RAS/RTK/PI 3 K，鳞状细胞分化，细胞周期和染色质重塑途径基因。已知致癌驱动因子和途径中的特定突变与较差的患者结局相关。我们的研究结果表明，转移性cSCC中的潜在治疗靶点包括PIK 3CA、FGFR 3、BRAF和EGFR，与肺和头颈部SCC中报告的靶点相似，这表明可以开发临床试验来招募来自多个来源部位的SCC患者。我们对一组罕见的29例转移性cSCC进行了基因组学特征分析，并确定了一系列不同的致癌改变，这些改变可以指导这种疾病的未来研究。
A rare 5% of cutaneous squamous cell carcinomas metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs. We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy number alterations associated with metastatic cSCC. We determined significantly mutated, deleted and amplified genes and associated genomic alterations with clinical variables. The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with HPV. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin. We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease.