人类鼻窦肿瘤的错配修复缺陷和体细胞突变

发表日期：2022-01-21

Mismatch Repair Deficiency and Somatic Mutations in Human Sinonasal Tumors

人类鼻窦肿瘤的错配修复缺陷和体细胞突变

Sinonasal carcinomas are rare tumors with an overall poor prognosis. Due to limitations in local therapeutic approaches, systemic neo-adjuvant or adjuvant therapies are becoming increasingly important in order to improve patient outcome. This study aimed to examine potentially therapeutic targetable molecular alterations in different sinonasal tumors, including deficiency in mismatch repair proteins and microsatellite instability as well as driver mutations. According to our results, immunohistochemical (IHC) analysis of mismatch repair (MMR) proteins and sequencing-based panel analysis should be integrated into the diagnostics of clinically aggressive inverted sinonasal papilloma (ISP) and sinonasal squamous cell carcinoma (SNSCC) in order to enable the therapeutic possibility of a targeted therapy.

鼻窦癌是一种罕见的肿瘤，总体预后较差。由于局部治疗方法的局限性，为了改善患者预后，全身性新辅助或辅助治疗变得越来越重要。本研究旨在检查不同鼻窦肿瘤中潜在的治疗性靶向分子改变，包括错配修复蛋白和微卫星不稳定性以及驱动突变的缺陷。根据我们的研究结果，错配修复 (MMR) 蛋白的免疫组织化学 (IHC) 分析和基于测序的面板分析应整合到临床侵袭性鼻窦内翻性乳头状瘤 (ISP) 和鼻窦鳞状细胞癌 (SNSCC) 的诊断中，以使靶向治疗的治疗可能性。

细胞工厂

Due to limitations in local therapy approaches for sinonasal tumors, improvement in systemic therapies plays a pivotal role for prolongation of the patient’s survival. The aim of this study was to examine potential biomarkers, including deficiency in mismatch repair proteins (dMMR)/microsatellite instability (MSI-H) in sinonasal cancers and their precancerous lesions. A comprehensive analysis of 10 sinonasal cancer cell lines by whole exome sequencing, screening 174 sinonasal tumors by immunohistochemistry (IHC) for mismatch repair deficiency and next generation sequencing (NGS) of 136 tumor samples revealed a dMMR/MSI-H sinonasal squamous cell carcinoma (SNSCC) cell line based on a somatic missense mutation in MLH1 and an overall frequency of dMMR/MSI-H SNSCC of 3.2% (4/125). Targetable EGFR mutations were found in 89.3% (25/28) of inverted sinonasal papilloma (ISP) and in 60% (6/10) of ISP-associated carcinomas. While PIK3CA and EGFR mutations were not mutually exclusive, KRAS mutated tumors were an EGFR-wildtype. The effect of potential driver mutations in FGFR2, FGFR3, BRAF, HRAS, MAP2K1, PTEN, NOTCH1 and CARD11 need further investigation. Our results suggest that biomarker testing, including MMR-IHC and NGS panel analysis, should be integrated into the diagnostics of clinically aggressive ISPs and SNSCC to assess prognosis and facilitate therapeutic decisions.

三角细胞摇瓶

由于鼻窦肿瘤局部治疗方法的局限性，改善全身治疗对于延长患者的生存期起着关键作用。本研究的目的是检查潜在的生物标志物，包括鼻窦癌及其癌前病变中错配修复蛋白 (dMMR)/微卫星不稳定性 (MSI-H) 的缺乏。通过全外显子组测序对 10 种鼻窦癌细胞系进行综合分析，通过免疫组织化学 (IHC) 筛查 174 种鼻窦肿瘤错配修复缺陷，并对 136 种肿瘤样本进行二代测序 (NGS)，结果显示为 dMMR/MSI-H 鼻窦鳞状细胞癌。 SNSCC) 细胞系基于MLH1中的体细胞错义突变和 dMMR/MSI-H SNSCC 的总频率为 3.2% (4/125)。靶向EGFR在 89.3% (25/28) 的倒置鼻窦乳头状瘤 (ISP) 和 60% (6/10) 的 ISP 相关癌中发现了突变。虽然PIK3CA和EGFR突变并不相互排斥，但KRAS突变的肿瘤是EGFR野生型。FGFR2、FGFR3、BRAF、HRAS、MAP2K1、PTEN、NOTCH1和CARD11中潜在驱动突变的影响需要进一步研究。我们的研究结果表明，生物标志物测试，包括 MMR-IHC 和 NGS 面板分析，应整合到临床侵袭性 ISP 和 SNSCC 的诊断中，以评估预后并促进治疗决策。

In conclusion, we comprehensively analyzed and characterized sinonasal tumors based on their histomorphological characteristics and molecular properties in a cohort of 220 sinonasal tumors and 10 corresponding sinonasal cancer cell lines. The molecular subclassification, including immunhistochemical and sequencing-based diagnostic approaches, provides useful information for selecting an individualized therapeutic strategy. Besides the promising and therapeutically targetable EGFR mutant SNSCC subgroup, we confirm a dMMR/MSI subtype of SNSCC, which may confer clinical benefit to ICI treatment.

PETG血清培养基瓶

总之，我们在一组 220 个鼻窦肿瘤和 10 个相应的鼻窦癌细胞系中，基于它们的组织形态学特征和分子特性，全面分析和表征了鼻腔肿瘤。分子亚分类，包括免疫组化和基于测序的诊断方法，为选择个体化治疗策略提供了有用的信息。除了有希望且可治疗靶向的EGFR突变 SNSCC 亚组外，我们还确认了 SNSCC 的 dMMR/MSI 亚型，这可能为 ICI 治疗带来临床益处。