Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Boston University School of Medicine, Boston, MA 02118, USA.
Department of Surgery, University of California, San Francisco, San Francisco, CA 94115, USA; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Cell Rep. 2018 Apr 3;23(1):194-212.e6. doi: 10.1016/j.celrep.2018.03.063.
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
这项综合性的、多平台的泛癌症图谱研究对与吸烟和/或人乳头瘤病毒（HPV）相关的五个部位的鳞状细胞癌（SCC）进行了共定位和特征鉴定。SCC 存在 3q、5p 和其他反复出现的染色体拷贝数改变（CNAs）、DNA 突变和/或基因和 microRNA 的异常甲基化，这些与与鳞状细胞干性、上皮-间充质分化、生长、基因组完整性、氧化损伤、死亡和炎症相关的多基因程序的表达相关。低 CNA SCC 倾向于 HPV(+)，表现出过度甲基化，抑制 TET1 去甲基酶和 FANCF，先前与 SCC 的易感性相关，或携带影响 CASP8、RAS-MAPK 途径、染色质修饰因子和免疫调节分子的突变。我们发现驱动 ΔNp63 癌基因表达的替代启动子的低甲基化和嵌入的 miR944。免疫检查点、T 调节和髓系抑制细胞特征的共表达可能解释了免疫治疗效果降低的原因。这些发现支持了分子分类和治疗方法的可能性。
