Mismatch Repair Deficiency and Somatic Mutations in Human Sinonasal Tumors

被引：12

作者：

Hieggelke, Lena ^{[1
]}

Heydt, Carina ^{[1
]}

Castiglione, Roberta ^{[2
]}

Rehker, Jan ^{[1
]}

Merkelbach-Bruse, Sabine ^{[1
]}

Riobello, Cristina ^{[3
,5
]}

Llorente, Jose Luis ^{[4
]}

Hermsen, Mario A. ^{[3
]}

Buettner, Reinhard ^{[1
]}

机构：

[1] Univ Cologne, Univ Hosp Cologne, Inst Pathol, D-50937 Cologne, Germany

[2] Klinikum Stuttgart, Inst Pathol, D-70174 Stuttgart, Germany

[3] Inst Invest Sanitaria Principado Asturias, Dept Head & Neck Oncol, Oviedo 33011, Spain

[4] Hosp Univ Cent Asturias, Dept Otolaryngol, Oviedo 33011, Spain

[5] Univ Santiago de Compostela, Hlth Res Inst Santiago De Compostela IDIS, Ctr Res Mol Med & Chron Dis CIMUS, Gene Regulatory Control Dis Lab, Santiago De Compostela 15706, Spain

来源：

CANCERS | 2021年 / 13卷 / 23期

关键词：

sinonasal squamous cell carcinoma; microsatellite instability; mismatch repair deficiency; EGFR; SQUAMOUS-CELL-CARCINOMA; PAPILLOMAVIRUS-RELATED CARCINOMA; CYSTIC-LIKE FEATURES; MICROSATELLITE INSTABILITY; CARD11; MUTATIONS; EGFR MUTATIONS; HPV INFECTION; OPEN-LABEL; CANCER; HEAD;

D O I：

10.3390/cancers13236081

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Simple Summary 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. 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.

引用

页数：20