Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models.
Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models.
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DOI：
10.1002/ijc.33125
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发表时间：
2020-12-01
影响因子：
6.4
通讯作者：
Basu D
中科院分区：
文献类型：
--
作者：
Facompre ND;Rajagopalan P;Sahu V;Pearson AT;Montone KT;James CD;Gleber-Netto FO;Weinstein GS;Jalaly J;Lin A;Rustgi AK;Nakagawa H;Califano JA;Pickering CR;White EA;Windle BE;Morgan IM;Cohen RB;Gimotty PA;Basu D
人乳头状瘤病毒相关（HPV+）头颈部鳞状细胞癌（HNSCC）的治疗创新因临床前模型不足和缺乏准确的生物标志物而受损。这项研究建立了第一个充分表征的来自HPV+ HNSCC的患者来源的异种移植物（PDX）和类器官的小组，同时确定了模型对这种癌症类型的区别遗传特征的保真度。尽管移植率低，但全外显子组测序显示，PDX保留了现有细胞系中丢失的HPV+ HNSCC的多种区别特征，包括PIK 3CA突变、TRAF 3缺失和EGFR扩增缺失。移植的HPV+肿瘤经常含有NOTCH 1突变，从而为这种疾病的负面预后改变提供了新的模型。然后测试模型中的基因型-表型相关性，以预测已发表的临床队列中的肿瘤进展和生存。在快速生长模型中观察到的高肿瘤突变负荷（TMB）有助于确定TMB与HPV+和HPV−患者局部进展之间的新关联，该关联在HPV−病例中具有预后意义。此外，在来自具有致死结果的离群病例的PDX中发现的E7和p16 INK 4A水平降低导致在复发性HPV+ HNSCC中检测到相似的特征。来自癌症基因组图谱的转录数据用于证明由降低的E7水平预测的较低的E2 F靶基因表达具有作为疾病复发风险的生物标志物的潜力。我们的发现填补了HPV+ HNSCC临床前模型的关键空白，同时揭示了定量突变负荷和病毒癌基因功能用于生物标志物开发的新的潜在应用。
Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and absence of accurate biomarkers. This study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion, and absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotype-phenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a novel association between TMB and local progression in both HPV+ and HPV− patients that was prognostic in HPV− cases. In addition, reduced E7 and p16INK4A levels found in a PDX from an outlier case with lethal outcome led to detection of similar profiles among recurrent HPV+ HNSCCs. Transcriptional data from the Cancer Genome Atlas was used to demonstrate that the lower E2F target gene expression predicted by reduced E7 levels has potential as a biomarker of disease recurrence risk. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel potential applications of quantifying mutational burden and viral oncogene functions for biomarker development.
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影响因子：
10.3
作者：
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通讯作者：
Morris, Luc G. T.
影响因子：
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影响因子：
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作者：
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影响因子：
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Eder, T.;Hess, A. K.;Tinhofer, I
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Tinhofer, I
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Chera, Bhishamjit S.;Kumar, Sunil;Gupta, Gaorav P.
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