Vossen David M, Verhagen Caroline V M, van der Heijden Martijn, Essers Paul B M, Bartelink Harry, Verheij Marcel, Wessels Lodewyk F A, van den Brekel Michiel W M, Vens Conchita
Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Department of Head and Neck Oncology and Surgery, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Cancers (Basel). 2019 Mar 29;11(4):445. doi: 10.3390/cancers11040445.
About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, (62%), (51%), (30%) and (21%), were not associated with PFS. However, co-occurring and mutations were associated with short PFS (HR 2.24, = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring and mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies.
大约一半的晚期头颈部鳞状细胞癌（HNSCC）患者可通过放化疗治愈。患者的预后可能部分由HNSCC中的基因改变决定，这使得这些改变成为有前景的候选预后因素和/或治疗靶点。然而，在接受标准放化疗的患者中，它们与患者预后的相关性仍有待评估。因此，我们测试了在接受确定性铂类放化疗的晚期HNSCC患者中，频繁的基因改变是否与无进展生存期（PFS）相关。为此，我们对77例晚期口咽和下咽癌患者治疗前的冷冻肿瘤活检材料进行了靶向DNA测序。这提供了556个基因的体细胞点突变和拷贝数变异数据。最常发生突变的基因，（62%）、（51%）、（30%）和（21%），与PFS无关。然而，在人乳头瘤病毒（HPV）阴性肿瘤中，同时发生的和突变与短PFS相关（风险比[HR]2.24，=0.028）。此外，肿瘤突变负荷（体细胞点突变总和）显示出PFS降低的趋势（HR 1.9，=0.089），并且染色体不稳定（CIN）与较短的PFS相关（HR 2.3，=0.023），与HPV状态无关。我们的结果表明，肿瘤突变负荷、CIN标志物以及同时发生的和突变与晚期口咽和下咽HNSCC患者放化疗结果相关，从而突出了它们的预后潜力。鉴于它们与预后不良的关联以及与生物学靶点的联系，它们也可能识别出适合新型靶向治疗和免疫治疗的患者。
