Department of Diagnostic Sciences, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, United States of America.
Department of Otolaryngology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
PLoS One. 2014 Jan 21;9(1):e85619. doi: 10.1371/journal.pone.0085619. eCollection 2014.
Head and Neck Squamous Cell Carcinoma (HNSCC) encompasses malignancies that arise in the mucosa of the upper aerodigestive tract. Recent high throughput DNA sequencing revealed HNSCC genes mutations that contribute to several cancer cell characteristics, including dysregulation of cell proliferation and death, intracellular proinflammatory signaling, and autophagy. The PYRIN-domain containing NLR (Nucleotide-binding domain, Leucine rich Repeats - containing) proteins have recently emerged as pivotal modulators of cell death, autophagy, inflammation, and metabolism. Their close physiologic association with cancer development prompted us to determine whether mutations within the NLRP (PYRIN-containing NLR) gene family were associated with HNSCC genome instability and their clinicopathologic correlations. Catastrophic mutational events underlie cancer cell genome instability and mark a point-of-no-return in cancer cell development and generation of heterogeneity. The mutation profiles of 62 patients with primary conventional type HNSCC excluding other histologic variants were analyzed. Associations were tested using Fisher's Exact test or Mann-Whitney U test. Mutations in NLRP were associated with elevated genome instability as characterized by higher mutation rates. Clinically, NLRP mutations were more frequently found in HNSCC arising in the floor of mouth (50.0%) in comparison with HNSCC at other head and neck locations (14.8%). These mutations were clustered at the leucine rich repeats region of NLRP proteins, and affected NLRP genes were mostly localized at chromosomes 11p15.4 and 19q13.42-19q13.43. Twenty novel NLRP mutations were identified in HNSCC, and mutations in this group of genes were correlated with increased cancer cell genome mutation rates, and such features could be a potential molecular biomarker of HNSCC genome instability.
头颈部鳞状细胞癌（HNSCC）包括发生在上呼吸道黏膜的恶性肿瘤。最近高通量 DNA 测序显示，HNSCC 基因突变导致多种癌细胞特征，包括细胞增殖和死亡失调、细胞内促炎信号和自噬。含 PYIRIN 结构域的 NLR（核苷酸结合域，富含亮氨酸重复序列）蛋白最近被认为是细胞死亡、自噬、炎症和代谢的关键调节剂。它们与癌症发展的密切生理关联促使我们确定 NLRP（含 PYIRIN 的 NLR）基因家族内的突变是否与 HNSCC 基因组不稳定性及其临床病理相关性相关。灾难性的突变事件是癌细胞基因组不稳定的基础，标志着癌细胞发展和异质性产生的不可逆转点。分析了 62 例原发性常规型 HNSCC 患者（不包括其他组织学变异）的突变谱。使用 Fisher's 精确检验或 Mann-Whitney U 检验检验相关性。NLRP 的突变与较高的基因突变率为特征的基因组不稳定性相关。临床上，NLRP 突变在口底 HNSCC 中（50.0%）比其他头颈部位置的 HNSCC 更频繁发生（14.8%）。这些突变集中在 NLRP 蛋白的富含亮氨酸重复区，受影响的 NLRP 基因主要定位于 11p15.4 和 19q13.42-19q13.43 染色体上。在 HNSCC 中鉴定出 20 种新的 NLRP 突变，该组基因的突变与癌细胞基因组基因突变率增加相关，这些特征可能是 HNSCC 基因组不稳定性的潜在分子生物标志物。
