Novel receptor tyrosine kinase mutations in rare paranasal sinus cancers and their potential functional implications

Yıl 2023, Cilt: 62 Sayı: 1, 139 - 154, 15.03.2023

Bakiye Goker Bagca Sercan Göde Göksel Turhal Neslihan Pınar Özateş Ali Veral Cumhur Gündüz Çığır Avcı

https://doi.org/10.19161/etd.1262612

Öz

Objective: Paranasal sinus cancers are a very rare and heterogeneous group of diseases. Maxillary sinus squamous cell carcinoma is the most common anatomical and histological subtype of paranasal sinus cancers. The limited knowledge about the genetic profile of this cancer causes patients not to benefit from targeted therapy options. In our study, we aimed to identify receptor tyrosine kinase mutations in this rare cancer and to predict the possible functional effects of these mutations.
Materials and Methods: For this purpose, DNA isolation was performed from FFPE tissues belonging to the tumors of 30 cases, and the mutation profile of the cases was determined by next generation sequencing and bioinformatics analyses. The functional effects of the determined pathogenic/likely pathogenic variants were estimated by using different in silico tools.
Results: At least one pathogenic/likely pathogenic KIT, PDFGRA and RET mutations were identified in all cases. It was predicted that mutations in the catalytic region of the KIT gene would increase kinase activity, and it was suggested that this mechanism could play a driver role in paranasal sinus cancers and create a new therapy target. It has been suggested that the p.P567P and p.D1074D mutations in the PDFGRA gene may be the potential biomarkers that can be used in the early diagnosis of the tumor.
Conclusion: The determination that receptor tyrosine kinase mutations may play an important role in paranasal sinus cancers is crucial in terms of the potential to offer treatment approaches targeting increased kinase activity to these patients.

Anahtar Kelimeler

paranasal sinus cancer, maxillary sinus squamous cell carcinoma, next generation sequencing, receptor tyrosine kinase

Nadir paranazal sinüs kanserlerinde yeni tanımlanan reseptör tirozin kinaz mutasyonları ve potansiyel fonksiyonel etkileri

Öz

Amaç: Paranazal sinüs kanserleri oldukça nadir ve heterojen bir hastalık grubudur. Maksiler sinüs skuamoz hücreli karsinomu, paranazal sinüs kanserlerinin anatomik ve histolojik olarak en yaygın alt tipidir. Bu kanserin genetik profiline dair bilginin sınırlı olması, hastaların hedefli tedavi seçeneklerinden yararlanamamasına neden olmaktadır. Çalışmamızda bu nadir kanserdeki reseptör tirozin kinaz mutasyonlarının tanımlanması ve mutasyonların olası fonksiyonel etkilerinin tahmin edilmesi amaçlanmıştır.
Gereç ve Yöntem: Bu amaçla 30 olgunun tümörüne ait FFPE dokulardan DNA izolasyonu gerçekleştirildi, olguların mutasyon profili yeni nesil sekanslama yöntemi ve biyoinformatik değerlendirme ile belirlendi. Belirlenen patojenik/ olası patojenik varyantların fonksiyonel etkileri farklı in silico araçlar yardımıyla tahminlendi.
Bulgular: Olgularının tamamında en az bir adet patojenik/olası patojenik KIT, PDFGRA ve RET mutasyonu tanımlandı. KIT geninin katalitik bölgesindeki mutasyonların kinaz aktivitesini arttıracağı tahmin edildi ve bu mekanizmanın paranazal sinüs kanserlerinde sürücü rol oynayabileceği ve yeni bir tedavi hedefi oluşturabileceği önerildi. PDFGRA genindeki p.P567P ve p.D1074D mutasyonlarının tümörün erken tanısında kullanılabilecek potansiyel biyobelitrteçler olabileceği önerildi.
Sonuç: Reseptör tirozin kinaz mutasyonlarının paranazasl sinüs kanserlerinde de önemli rol oynayabileceğinin belirlenmiş olması özellikle artmış kinaz aktivitesini hedefleyen tedavi yaklaşımlarını bu olguların erişimine sunma potansiyeli taşıması bakımından oldukça önemlidir.

Anahtar Kelimeler

paranazal sinüs kanseri, maksiler sinüs skuamoz hücreli karsinomu, yeni nesil sekanslama, reseptör tirozin kinaz

Kaynakça

• Rahman QB, Iocca O, Kufta K, Shanti RM. Global Burden of Head and Neck Cancer. Oral Maxillofac. Surg. Clin. North Am. 2020; 32(3):367-75. doi: 10.1016/j.coms.2020.04.002.
• El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (ed). WHO Classification of Head and Neck Tumours WHO/IARC Classification of Tumours, Vol. 9, 4th ed. IARC Press Lyon. 2017.
• Elgart K, Faden DL. Sinonasal Squamous Cell Carcinoma: Etiology, Pathogenesis, and the Role of Human Papilloma Virus. Curr Otorhinolaryngol Rep. 2020; 8(2):111-9. doi: 10.1007/s40136-020-00279-6.
• Lund VJ, Clarke PM, Swift AC, McGarry GW, Kerawala C, Carnell D. Nose and paranasal sinus tumours: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016; 130(S2):111-8. doi: 10.1017/s0022215116000530.
• Yasukawa S, Kano S, Hatakeyama H, Nakamaru Y, Takagi D, Mizumachi T, Suzuki M, Suzuki T, Nakazono A, Tanaka S, et al. Genetic mutation analysis of the malignant transformation of sinonasal inverted papilloma by targeted amplicon sequencing. Int J Clin Oncol. 2018; 23(5):835-43. doi: 10.1007/s10147-018-1296-1. Cited: in: : PMID: 29779136.
• Choe JY, Nam SJ, Yun JY, Kim JE. Expression of c-met is different along the location and associated with lymph node metastasis of head and neck carcinoma. Korean J Pathol. 2012; 46(6):515-22. doi: 10.4132/KoreanJPathol.2012.46.6.515.
• Göker Bagca B. Paranazal sinüs karsinogenezinde tedavi hedefi oluşturabilecek genomik profilin belirlenmesi (Doktora tezi). Ege Üniversitesi. 2021.
• Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, Massouras A. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35(11):1978-80. doi: 10.1093/bioinformatics/bty897.
• Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, Tsimberidou AM, Vnencak-Jones CL, Wolff DJ, Younes A, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J. Mol. Diagnostics. 2017;19(1):4-23. doi: 10.1016/j.jmoldx.2016.10.002.
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5):405-24. doi: 10.1038/gim.2015.30.
• Chou CH, Shrestha S, Yang CD, Chang NW, Lin YL, Liao KW, Huang WC, Sun TH, Tu SJ, Lee WH, et al. MiRTarBase update 2018: A resource for experimentally validated microRNA-target interactions. Nucleic Acids Res. 2018; 46(D1):296-302. doi: 10.1093/nar/gkx1067.
• Chauhan JS, Mishra NK, Raghava GPS. Identification of ATP binding residues of a protein from its primary sequence. BMC Bioinformatics. 2009;10:434. doi: 10.1186/1471-2105-10-434.
• Rodrigues CHM, Ascher DB, Pires DEV. Kinact: A computational approach for predicting activating missense mutations in protein kinases. Nucleic Acids Res. 2018;46(W1):127-32. doi: 10.1093/nar/gky375.
• Abbasi WA, Yaseen A, Hassan FU, Andleeb S, Minhas FUAA. ISLAND: in-silico proteins binding affinity prediction using sequence information. BioData Min. 2020;13(1):20. doi: 10.1186/s13040-020-00231-w.
• Ségaliny AI, Tellez-Gabriel M, Heymann MF, Heymann D. Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers. J. Bone Oncol. 2015; 4(1):1-12. doi: 10.1016/j.jbo.2015.01.001.
• Puputti M, Tynninen O, Sihto H, Blom T, Mäenpää H, Isola J, Paetau A, Joensuu H, Nupponen NN. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res. 2006; 4(12):927-34. doi: 10.1158/1541-7786.MCR-06-0085.
• Liang J, Wu YL, Chen BJ, Zhang W, Tanaka Y, Sugiyama H. The C-Kit receptor-mediated signal transduction and tumor-related diseases. Int. J. Biol. Sci. 2013; 9(5):435-43. doi: 10.7150/ijbs.6087.
• Ahn R, Ursini-Siegel J. Clinical potential of kinase inhibitors in combination with immune checkpoint inhibitors for the treatment of solid tumors. Int. J. Mol. Sci. 2021; 22(5):2608. doi: 10.3390/ijms22052608.
• McDermott U, Ames RY, Iafrate AJ, Maheswaran S, Stubbs H, Greninger P, Mccutcheon K, Milano R, Tam A, Lee DY, et al. Ligand-dependent platelet-derived growth factor receptor (PDGFR)-α activation sensitizes rare lung cancer and sarcoma cells to PDGFR kinase inhibitors. Cancer Res. 2009;69(9):3937-46. doi: 10.1158/0008-5472.CAN-08-4327.
• Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003; 299(5607):708-10. doi: 10.1126/science.1079666.
• Hantschel O, Grebien F, Superti-Furga G. The growing arsenal of ATP-competitive and allosteric inhibitors of BCR-ABL. Cancer Res. 2012;72(19):4890-5. doi: 10.1158/0008-5472.CAN-12-1276.
• Takahashi M, Kawai K, Asai N. Roles of the RET Proto-oncogene in Cancer and Development. JMA J. 2020; 3(3):175-81. doi: 10.31662/jmaj.2020-0021.
• Yang J, Lin Y, Huang Y, Jin J, Zou S, Zhang X, Li H, Feng T, Chen J, Zuo Z, et al. Genome landscapes of rectal cancer before and after preoperative chemoradiotherapy. Theranostics. 2019;9(23): 6856–66.doi: 10.7150/thno.37794.
• George RE, Sanda T, Hanna M, Fröhling S, Luther W, Zhang J, Ahn Y, Zhou W, London WB, McGrady P, et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008; 455(7215):975-8. doi: 10.1038/nature07397.
• Zhu VW, Schrock AB, Bosemani T, Benn BS, Ali SM, Ou SHI. Dramatic response to alectinib in a lung cancer patient with a novel VKORC1L1-ALK fusion and an acquired ALK T1151K mutation. Lung Cancer Targets Ther. 2018; 9: 111-6. doi: 10.2147/LCTT.S186804.
• Mansour H, Ouhajjou A, Bajic VB, Incitti R. Next-Generation Sequencing at High Sequencing Depth as a Tool to Study the Evolution of Metastasis Driven by Genetic Change Events of Lung Squamous Cell Carcinoma. Front Oncol. 2020; 10: 1215. doi: 10.3389/fonc.2020.01215.
• Betge J, Kerr G, Miersch T, Leible S, Erdmann G, Galata CL, Zhan T, Gaiser T, Post S, Ebert MP, et al. Amplicon sequencing of colorectal cancer: Variant calling in frozen and formalin-fixed samples. PLoS One. 2015; 10(5): e0127146. doi: 10.1371/journal.pone.0127146.
• Bossi RT, Saccardo MB, Ardini E, Menichincheri M, Rusconi L, Magnaghi P, Orsini P, Avanzi N, Borgia AL, Nesi M, et al. Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors. Biochemistry. 2010; 49(32):6813-25. doi: 10.1021/bi1005514.
• Horn L, Pao W. EML4-ALK: Honing in on a new target in non-small-cell lung cancer. J. Clin. Oncol. 2009; 27(26):4232-5. doi: 10.1200/JCO.2009.23.6661.