Artikel
Disruptive TP53 mutations, gene expression patterns and HPV16 E6*I status define subgroups of head and neck cancer (HNSCC) associated with lymph node metastasis and survival
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Veröffentlicht: | 30. März 2016 |
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Gliederung
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Background: Classification of HNSCC regarding mutated genes, gene expression patterns, and HPV16 DNA and RNA status may facilitate patient stratification.
Methods: HNSCC of consecutively recruited patients underwent HPV-DNA genotyping, HPV16-RNA (E6*I) detection, targeted sequencing (n=226; 50 genes, Ion Torrent), and gene expression profiling (n=270; Illumina HT12). Unsupervised gene-expression analysis was done by consensus clustering.
Results: HPV16 E6*I expressing (DNA+RNA+) HNSCC are molecularly distinct from HPV-negative (DNA-). They have elevated expression of cell cycle genes and carry TP53 mutations very rarely (1/28=3.6%). HNSCC without HPV16 E6*I transcripts (DNA+RNA-) are similar to DNA- tumors in gene expression and TP53 mutation frequency (8/17=47%, and 72/167=43%). Disruptive TP53 mutations (TP53mut) are linked to poor prognosis (OS: HR=2.0; CI95% 1.1-3.6; P=0.03; PFS: HR=1.9; CI95% 1.2-3.2; P=0.01), adjusting for UICC stage, age, tumor site, treatment, pack-years smoked, alcohol use, HPV16 status. We identify four gene expression clusters. Adjusting for UICC stage, age, tumor site, treatment, pack-years smoked, alcohol use, and HPV16 status they significantly differ in overall survival (OS; P=0.04). One cluster with high expression of immune response genes (IR) contains most DNA+RNA+ HNSCC (27/35=77%). Independent on HPV16 status and primary tumor site HNSCC with either TP53mut or belonging to the IR cluster are characterized by higher frequent lymph node metastasis (OR=2.6, CI95% 1.2-6.0; P=0.01, and OR=5.7, CI95% 2.2-18.0; P<0.001).
Conclusions: The IR gene expression cluster and TP53mut in HNSCC are associated with lymph node metastasis. HNSCC patient stratification can be improved by elucidation of HPV16 E6*I and TP53mut status.
Supported by: The study was supported by the grants LIFE-006 B7 and LIFE-007 D9 of the Leipzig Research Center for Civilization Diseases (LIFE), University Leipzig. LIFE is funded by the European Union, the European Fund for Regional Development (EFRE), and the Free State of Saxony.
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