Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype.
Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype.
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DOI：
10.1016/j.ebiom.2017.02.025
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发表时间：
2017-03
期刊：
影响因子：
11.1
通讯作者：
Gevaert O
中科院分区：
文献类型：
--
作者：
Brennan K;Koenig JL;Gentles AJ;Sunwoo JB;Gevaert O
头颈部鳞状细胞癌（HNSCC）大致分为与人乳头瘤病毒（HPV）感染相关的HNSCC和HPV阴性的HNSCC，后者通常与吸烟相关。HPV阴性HNSCC的一个子集发生在没有吸烟史的患者中，然而，这些病因学上的“非典型”HNSCC不成比例地发生在口腔和女性患者中，表明了独特的病因。为了研究临床和分子异质性的决定因素，我们进行了无监督聚类，根据表观遗传学（DNA甲基化）失调基因的特征，将528例来自癌症基因组图谱（TCGA）的HNSCC患者分类为假定的内在亚型。HNSCC可分为5种亚型，包括1种HPV阳性亚型、2种吸烟相关亚型和2种非典型亚型。一个非典型亚型是特别基因组稳定，但功能广泛的基因沉默与“CpG岛甲基化表型”（CIMP）。这种“CIMP-Atypical”亚型的进一步区别特征包括与促炎性M1巨噬细胞和CD 8 + T细胞浸润相关的抗病毒基因表达谱、CASP 8突变以及对应于正常SOX 2拷贝数和SOX 2 OT超甲基化的良好分化状态。我们开发了一种CIMP-Atypical亚型的基因表达分类器，可以对两个独立患者队列中的非典型疾病特征进行分类，证明了该亚型的可重复性。总之，这些发现提供了前所未有的证据，表明非典型HNSCC在分子上是不同的，并假定CIMP-Atypical亚型是一种独特的临床实体，可能由慢性炎症引起。我们确定了五种不同病因的头颈部鳞状细胞癌DNA甲基化亚型。一种亚型似乎与吸烟或HPV无关，可能代表一种独特的病因实体。这种亚型的独特分子特征包括CIMP、CASP 8突变和抗病毒免疫应答。为了确定确定头颈部鳞状细胞癌（HNSCC）临床和生物学变异性的因素，我们根据其表观遗传特征将患者分为亚型，揭示了五种亚型，包括先前确定的亚型。我们专注于发现与先前归因于“非典型”HNSCC的临床特征相匹配的亚型，即，HNSCC不是由吸烟或HPV的经典HNSCC风险因素引起的。该亚型在多种分子数据类型中具有生物学差异，并且在独立患者人群中可重现。我们假设这种“CIMP-非典型”亚型代表了一种临床上不同的HNSCC亚型，原因不明。
Head and neck squamous cell carcinoma (HNSCC) is broadly classified into HNSCC associated with human papilloma virus (HPV) infection, and HPV negative HNSCC, which is typically smoking-related. A subset of HPV negative HNSCCs occur in patients without smoking history, however, and these etiologically ‘atypical’ HNSCCs disproportionately occur in the oral cavity, and in female patients, suggesting a distinct etiology. To investigate the determinants of clinical and molecular heterogeneity, we performed unsupervised clustering to classify 528 HNSCC patients from The Cancer Genome Atlas (TCGA) into putative intrinsic subtypes based on their profiles of epigenetically (DNA methylation) deregulated genes. HNSCCs clustered into five subtypes, including one HPV positive subtype, two smoking-related subtypes, and two atypical subtypes. One atypical subtype was particularly genomically stable, but featured widespread gene silencing associated with the ‘CpG island methylator phenotype’ (CIMP). Further distinguishing features of this ‘CIMP-Atypical’ subtype include an antiviral gene expression profile associated with pro-inflammatory M1 macrophages and CD8+ T cell infiltration, CASP8 mutations, and a well-differentiated state corresponding to normal SOX2 copy number and SOX2OT hypermethylation. We developed a gene expression classifier for the CIMP-Atypical subtype that could classify atypical disease features in two independent patient cohorts, demonstrating the reproducibility of this subtype. Taken together, these findings provide unprecedented evidence that atypical HNSCC is molecularly distinct, and postulates the CIMP-Atypical subtype as a distinct clinical entity that may be caused by chronic inflammation. We identified five etiologically distinct DNA methylation subtypes of head and neck squamous cell carcinoma. One subtype appears not to be associated with smoking or HPV, and may represent a distinct etiological entity. Distinctive molecularly features of this subtype include CIMP, CASP8 mutations, and antiviral immune response. To identify factors that define clinical and biological variability in head and neck squamous cell carcinoma (HNSCC), we clustered patients into subtypes based on their epigenetic profiles, revealing five subtypes, including previously identified subtypes. We focus on discovery of a subtype that matches the clinical characteristics previously ascribed to ‘atypical’ HNSCC, i.e., HNSCC that is not caused by the classic HNSCC risk factors of smoking or HPV. This subtype is biologically distinct across multiple molecular data types, and was reproducible in independent patient populations. We postulate that this ‘CIMP-Atypical’ subtype represents a clinically distinct HNSCC subtype of unknown cause.