Mutational landscape of aggressive cutaneous squamous cell carcinoma.
Mutational landscape of aggressive cutaneous squamous cell carcinoma.
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DOI：
10.1158/1078-0432.ccr-14-1768
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发表时间：
2014-12-15
期刊：
影响因子：
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通讯作者：
Frederick MJ
中科院分区：
文献类型：
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作者：
Pickering CR;Zhou JH;Lee JJ;Drummond JA;Peng SA;Saade RE;Tsai KY;Curry JL;Tetzlaff MT;Lai SY;Yu J;Muzny DM;Doddapaneni H;Shinbrot E;Covington KR;Zhang J;Seth S;Caulin C;Clayman GL;El-Naggar AK;Gibbs RA;Weber RS;Myers JN;Wheeler DA;Frederick MJ
侵袭性皮肤鳞状细胞癌（cSCC）通常是毁容和致命的疾病。目前对驱动侵袭性cSCC的突变知之甚少。对39例侵袭性cSCC进行了全外显子组测序，以确定驱动基因和新的治疗靶点。通过MutSig或基于失活突变偏倚特异性鉴定候选肿瘤抑制因子的互补方法鉴定显著突变基因。尽管紫外线照射引起的突变背景非常高，但我们确定了23个候选驱动因素，包括众所周知的癌症相关基因TP53、CDKN2A、NOTCH1、AJUBA、HRAS、CASP8、FAT1和KMT2C （MLL3）。三种新的候选肿瘤抑制因子NOTCH2、PARD3和RASA1被认为与癌症或分化有关，也被确定为cSCC的可能驱动因素。KMT2C突变与预后不良和骨侵袭增加有关。cSCC的突变谱与头颈部鳞状细胞癌相似，以抑癌基因为主。这些结果提高了理解这种疾病的基础，并有助于识别和治疗侵袭性cSCC。
Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. Whole exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. Despite the very high mutational background caused by UV exposure, 23 candidate drivers were identified including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3 and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.