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Mismatch Repair Deficiency and Somatic Mutations in Human Sinonasal Tumors

人類鼻竇腫瘤的錯(cuò)配修復(fù)缺陷和體細(xì)胞突變

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.

鼻竇癌是一種罕見的腫瘤，總體預(yù)后較差。由于局部治療方法的局限性，為了改善患者預(yù)后，全身性新輔助或輔助治療變得越來越重要。本研究旨在檢查不同鼻竇腫瘤中潛在的治療性靶向分子改變，包括錯(cuò)配修復(fù)蛋白和微衛(wèi)星不穩(wěn)定性以及驅(qū)動(dòng)突變的缺陷。根據(jù)我們的研究結(jié)果，錯(cuò)配修復(fù) (MMR) 蛋白的免疫組織化學(xué) (IHC) 分析和基于測序的面板分析應(yīng)整合到臨床侵襲性鼻竇內(nèi)翻性乳頭狀瘤 (ISP) 和鼻竇鱗狀細(xì)胞癌 (SNSCC) 的診斷中，以使靶向治療的治療可能性。

細(xì)胞工廠

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.

三角細(xì)胞搖瓶

由于鼻竇腫瘤局部治療方法的局限性，改善全身治療對于延長患者的生存期起著關(guān)鍵作用。本研究的目的是檢查潛在的生物標(biāo)志物，包括鼻竇癌及其癌前病變中錯(cuò)配修復(fù)蛋白 (dMMR)/微衛(wèi)星不穩(wěn)定性 (MSI-H) 的缺乏。通過全外顯子組測序?qū)?10 種鼻竇癌細(xì)胞系進(jìn)行綜合分析，通過免疫組織化學(xué) (IHC) 篩查 174 種鼻竇腫瘤錯(cuò)配修復(fù)缺陷，并對 136 種腫瘤樣本進(jìn)行二代測序 (NGS)，結(jié)果顯示為 dMMR/MSI-H 鼻竇鱗狀細(xì)胞癌。 SNSCC) 細(xì)胞系基于MLH1中的體細(xì)胞錯(cuò)義突變和 dMMR/MSI-H SNSCC 的總頻率為 3.2% (4/125)。靶向EGFR在 89.3% (25/28) 的倒置鼻竇乳頭狀瘤 (ISP) 和 60% (6/10) 的 ISP 相關(guān)癌中發(fā)現(xiàn)了突變。雖然PIK3CA和EGFR突變并不相互排斥，但KRAS突變的腫瘤是EGFR野生型。FGFR2、FGFR3、BRAF、HRAS、MAP2K1、PTEN、NOTCH1和CARD11中潛在驅(qū)動(dòng)突變的影響需要進(jìn)一步研究。我們的研究結(jié)果表明，生物標(biāo)志物測試，包括 MMR-IHC 和 NGS 面板分析，應(yīng)整合到臨床侵襲性 ISP 和 SNSCC 的診斷中，以評估預(yù)后并促進(jìn)治療決策。

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血清培養(yǎng)基瓶

總之，我們在一組 220 個(gè)鼻竇腫瘤和 10 個(gè)相應(yīng)的鼻竇癌細(xì)胞系中，基于它們的組織形態(tài)學(xué)特征和分子特性，全面分析和表征了鼻腔腫瘤。分子亞分類，包括免疫組化和基于測序的診斷方法，為選擇個(gè)體化治療策略提供了有用的信息。除了有希望且可治療靶向的EGFR突變 SNSCC 亞組外，我們還確認(rèn)了 SNSCC 的 dMMR/MSI 亞型，這可能為 ICI 治療帶來臨床益處。

關(guān)鍵詞：sinonasal squamous cell carcinoma,microsatellite instability,mismatch repair deficiency,EGFR鼻竇鱗狀細(xì)胞癌,微衛(wèi)星不穩(wěn)定性,錯(cuò)配修復(fù)缺陷,表皮生長因子受體

來源：MDPI https://www.mdpi.com/2072-6694/13/23/6081/htm