Apostolos Klinakis1, Theodoros Rampias2. 1. Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece. Electronic address: aklinakis@bioacademy.gr. 2. Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece. Electronic address: trampias@bioacademy.gr.
Abstract
BACKGROUND: Head and neck squamous cell carcinoma is a heterogeneous disease with respect to the anatomic site of the primary tumor. On the other hand, it is highly recurrent, and once metastatic, it is associated with poor prognosis. TP53 is the most commonly mutated gene in primary disease. TP53 mutations occur in different structural elements of the protein while the biological outcome can be diverse. METHODS: Here we aimed to find differences in the mutation profile of TP53 in primary and metastatic disease and the impact of TP53 mutations in metastasis, specific copy number alterations, tumor mutation burden and response to immune checkpoint inhibitors. Somatic mutation and clinical data for 512 primary and 134 metastatic biopsies were studied. FINDINGS: Overall TP53 mutation frequency is significantly lower in metastases compared to primary tumors. One the other hand, missense mutations in the DNA binding region are significantly enriched in metastases and are associated with a common fragile site in chromosome 11, leading to amplification and overexpression of genes with established role in metastasis. Finally, TP53 mutations are associated with higher TMB score in metastatic but not primary tumors, and poorer response to immune checkpoint inhibitors for the latter. INTERPRETATION: TP53 mutations affect clinical and molecular aspects of head and neck tumorigenesis including metastasis, genetic alterations and therapeutic response. FUNDING: This work was supported by a Horizon 2020 grant (801347) to AK, and a Greek General Secretariat for Research and Technology and the Hellenic Foundation for Research and Innovation grant (472-EpiNotch) to TR.
BACKGROUND: Head and neck squamous cell carcinoma is a heterogeneous disease with respect to the anatomic site of the primary tumor. On the other hand, it is highly recurrent, and once metastatic, it is associated with poor prognosis. TP53 is the most commonly mutated gene in primary disease. TP53 mutations occur in different structural elements of the protein while the biological outcome can be diverse. METHODS: Here we aimed to find differences in the mutation profile of TP53 in primary and metastatic disease and the impact of TP53 mutations in metastasis, specific copy number alterations, tumor mutation burden and response to immune checkpoint inhibitors. Somatic mutation and clinical data for 512 primary and 134 metastatic biopsies were studied. FINDINGS: Overall TP53 mutation frequency is significantly lower in metastases compared to primary tumors. One the other hand, missense mutations in the DNA binding region are significantly enriched in metastases and are associated with a common fragile site in chromosome 11, leading to amplification and overexpression of genes with established role in metastasis. Finally, TP53 mutations are associated with higher TMB score in metastatic but not primary tumors, and poorer response to immune checkpoint inhibitors for the latter. INTERPRETATION:TP53 mutations affect clinical and molecular aspects of head and neck tumorigenesis including metastasis, genetic alterations and therapeutic response. FUNDING: This work was supported by a Horizon 2020 grant (801347) to AK, and a Greek General Secretariat for Research and Technology and the Hellenic Foundation for Research and Innovation grant (472-EpiNotch) to TR.
Authors: Barbara Burtness; Kevin J Harrington; Richard Greil; Denis Soulières; Makoto Tahara; Gilberto de Castro; Amanda Psyrri; Neus Basté; Prakash Neupane; Åse Bratland; Thorsten Fuereder; Brett G M Hughes; Ricard Mesía; Nuttapong Ngamphaiboon; Tamara Rordorf; Wan Zamaniah Wan Ishak; Ruey-Long Hong; René González Mendoza; Ananya Roy; Yayan Zhang; Burak Gumuscu; Jonathan D Cheng; Fan Jin; Danny Rischin Journal: Lancet Date: 2019-11-01 Impact factor: 79.321
Authors: Amarinder Singh Thind; Bruce Ashford; Dario Strbenac; Jenny Mitchell; Jenny Lee; Simon A Mueller; Elahe Minaei; Jay R Perry; Sydney Ch'ng; N Gopalakrishna Iyer; Jonathan R Clark; Ruta Gupta; Marie Ranson Journal: Front Oncol Date: 2022-08-02 Impact factor: 5.738