Machnicki Marcin M, Rzepakowska Anna, Janowska Joanna I, Pepek Monika, Krop Alicja, Pruszczyk Katarzyna, Stawinski Piotr, Rydzanicz Malgorzata, Grzybowski Jakub, Gornicka Barbara, Wnuk Maciej, Ploski Rafal, Osuch-Wojcikiewicz Ewa, Stoklosa Tomasz
Department of Tumor Biology and Genetics, Medical University of Warsaw, Warsaw, Poland.
Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland.
Front Oncol. 2022 May 19;12:768954. doi: 10.3389/fonc.2022.768954. eCollection 2022.
Hypopharyngeal cancer is a poorly characterized type of head and neck squamous cell carcinoma (HNSCC) with bleak prognosis and only few studies focusing specifically on the genomic profile of this type of cancer. We performed molecular profiling of 48 HPV (Human Papilloma Virus)-negative tumor samples including 23 originating from the hypopharynx and 25 from the larynx using a targeted next-generation sequencing approach. Among genes previously described as significantly mutated, , and were found to be most frequently mutated. We also found that more than three-quarters of our patients harbored candidate actionable or prognostic alterations in genes belonging to RTK/ERK/PI3K, cell-cycle, and DNA-damage repair pathways. Using previously published data we compared 67 hypopharyngeal cancers to 595 HNSCC from other sites and found no prominent differences in mutational frequency except for and genes. Since we observed relatively frequent mutations of in our dataset, we analyzed their role, , by generating a -mutant hypopharyngeal cancer cell line FaDu with CRISPR-Cas9. We demonstrated that loss-of-function mutations resulted in increased colony formation and proliferation, in concordance with previously published results. In summary, our results show that the mutational profile of hypopharyngeal cancers might be similar to the one observed for other head and neck cancers with respect to minor differences and includes multiple candidate actionable and prognostic genetic alterations. We also demonstrated, for the first time, that the gene may play a role of tumor suppressor in HNSCC, which opens new possibilities in the search for new targeted treatment approaches.
下咽癌是一种特征不明的头颈部鳞状细胞癌（HNSCC），预后不佳，仅有少数研究专门关注这类癌症的基因组概况。我们使用靶向二代测序方法对48例人乳头瘤病毒（HPV）阴性肿瘤样本进行了分子分析，其中23例起源于下咽，25例起源于喉部。在先前描述为有显著突变的基因中，发现[具体基因1]、[具体基因2]和[具体基因3]突变最为频繁。我们还发现，超过四分之三的患者在属于RTK/ERK/PI3K、细胞周期和DNA损伤修复途径的基因中存在可能具有可操作性或预后意义的改变。利用先前发表的数据，我们将67例下咽癌与595例其他部位的HNSCC进行比较，发现除了[具体基因4]和[具体基因5]外，突变频率没有显著差异。由于我们在数据集中观察到[具体基因6]相对频繁的突变，我们通过CRISPR-Cas9技术构建了[具体基因6]突变的下咽癌细胞系FaDu，分析了它们的作用，即[具体作用]。我们证明，[具体基因6]功能缺失突变导致集落形成和增殖增加，这与先前发表的结果一致。总之，我们的结果表明，下咽癌的突变谱与其他头颈部癌症的突变谱可能相似，仅存在细微差异，并且包括多个可能具有可操作性和预后意义的基因改变。我们还首次证明，[具体基因6]基因可能在HNSCC中发挥肿瘤抑制作用，这为寻找新的靶向治疗方法开辟了新的可能性。
