Inter- and intra-tumor heterogeneity of SMAD4 loss in head and neck squamous cell carcinomas
Inter- and intra-tumor heterogeneity of SMAD4 loss in head and neck squamous cell carcinomas
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DOI：
10.1002/mc.22958
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发表时间：
2019-05-01
影响因子：
4.6
通讯作者：
Wang, Xiao-Jing
中科院分区：
文献类型：
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作者：
Hernandez, Ariel L.;Wang, Ying;Wang, Xiao-Jing
关于SMAD4在人头颈部鳞状细胞癌（HNSCC）中丢失的频率的报道差异显著。我们已经证明SMAD4缺失有助于HNSCC的发生和进展。因此，准确检测SMAD4基因缺失对于确定个性化医疗的预后和治疗干预至关重要。我们开发了SMAD4荧光原位杂交（FISH）测定法，以在原发性HNSCC标本和源自HNSCC的患者来源的异种移植（PDX）肿瘤的单细胞水平上鉴定染色体SMAD4损失。SMAD4杂合丢失在35%的原发性HNSCC和41.3%的PDX肿瘤中检测到。此外，4.3%的PDX肿瘤具有SMAD4纯合丢失。这些SMAD 4丢失的频率与癌症基因组图谱（TCGA）中的相似。然而，我们发现每个肿瘤内的细胞之间SMAD4损失（部分或完全）的显著异质性。我们还发现，非整倍体（单体性和多体性）的贡献很大，如何定义染色体SMAD4缺失。此外，在培养的PDX肿瘤中，SMAD4突变体细胞胜过SMAD4野生型细胞，导致建立具有部分或完全基因组SMAD4损失的同质SMAD4突变体HNSCC细胞系，表明SMAD4突变体细胞的存活优势。总之，我们的研究揭示了HNSCC中SMAD 4染色体丢失的肿瘤间和肿瘤内异质性。此外，SMAD4 FISH检测为SMAD4染色体丢失的未来临床诊断提供了一个平台，该平台可能用作癌症患者预后和治疗干预的分子标志物。
Reports regarding the frequency of SMAD4 loss in human head and neck squamous cell carcinoma (HNSCC) vary significantly. We have shown that SMAD4 deletion contributes to HNSCC initiation and progression. Therefore, accurately detecting genetic SMAD4 loss is critical to determine prognosis and therapeutic interventions in personalized medicine. We developed a SMAD4 fluorescence in situ hybridization (FISH) assay to identify chromosomal SMAD4 loss at the single cell level of primary HNSCC specimens and patient derived xenograft (PDX) tumors derived from HNSCCs. SMAD4 heterozygous loss was detected in 35% of primary HNSCCs and 41.3% of PDX tumors. Additionally, 4.3% of PDX tumors had SMAD4 homozygous loss. These frequencies of SMAD4 loss were similar to those in The Cancer Genome Atlas (TCGA). However, we identified significant heterogeneities of SMAD4 loss (partial or complete) among cells within each tumor. We also found that aneuploidy (monosomy and polysomy) contributed greatly to how to define chromosomal SMAD4 deletion. Furthermore, in cultured PDX tumors, SMAD4 mutant cells outcompeted SMAD4 wildtype cells, resulting in establishing homogenous SMAD4 mutant HNSCC cell lines with partial or complete genomic SMAD4 loss, suggesting a survival advantage of SMAD4 mutant cells. Taken together, our study reveals inter- and intra-tumor heterogeneities of SMAD4 chromosomal loss in HNSCCs. Further, SMAD4 FISH assay provides a platform for future clinical diagnosis of SMAD4 chromosomal loss that potentially serves as a molecular marker for prognosis and therapeutic intervention in cancer patients.