Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patient Cohort
2.2. Tissue Samples
2.3. DNA Extraction
2.4. NGS Analysis of SNVs
2.5. Bioinformatics and Computational Analysis of NGS Data
2.6. Statistical Analysis
3. Results
3.1. Histology and Immunohistochemical Expression of CD117
3.2. SNV Annotation and Clinical Interpretation
3.3. Associations of KIT Mutations with CD117 Protein Expression
3.4. Associations of Pathogenic SNVs with Clinical Factors and Treatment Outcomes
4. Discussion
4.1. Literature Review
4.2. Pathogenic Variants
4.3. Associations of Pathogenic Variants with DFS
4.4. Variants of Uncertain Clinical Significance
4.5. Germline Variants
4.6. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Rich, A.L. Epidemiology of thymoma. J. Thorac. Dis. 2020, 12, 7531–7535. [Google Scholar] [CrossRef] [PubMed]
- de Jong, W.K.; Blaauwgeers, J.L.; Schaapveld, M.; Timens, W.; Klinkenberg, T.J.; Groen, H.J. Thymic epithelial tumours: A population-based study of the incidence, diagnostic procedures and therapy. Eur. J. Cancer 2008, 44, 123–130. [Google Scholar] [CrossRef] [PubMed]
- WHO Classification of Tumours Editorial Board. Thoracic Tumours [Internet], 5th ed.; International Agency for Research on Cancer: Lyon, France, 2021; Volume 5, Available online: https://tumourclassification.iarc.who.int/chapters/35 (accessed on 9 March 2022).
- Weis, C.A.; Yao, X.; Deng, Y.; Detterbeck, F.C.; Marino, M.; Nicholson, A.G.; Huang, J.; Strobel, P.; Antonicelli, A.; Marx, A.; et al. The impact of thymoma histotype on prognosis in a worldwide database. J. Thorac. Oncol. 2015, 10, 367–372. [Google Scholar] [CrossRef] [Green Version]
- Roden, A.C.; Yi, E.S.; Cassivi, S.D.; Jenkins, S.M.; Garces, Y.I.; Aubry, M.C. Clinicopathological features of thymic carcinomas and the impact of histopathological agreement on prognostical studies. Eur. J. Cardiothorac. Surg. 2013, 43, 1131–1139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Girard, N.; Ruffini, E.; Marx, A.; Faivre-Finn, C.; Peters, S.; Committee, E.G. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2015, 26, v40–v55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tateo, V.; Manuzzi, L.; Parisi, C.; De Giglio, A.; Campana, D.; Pantaleo, M.A.; Lamberti, G. An Overview on Molecular Characterization of Thymic Tumors: Old and New Targets for Clinical Advances. Pharmaceuticals 2021, 14, 316. [Google Scholar] [CrossRef] [PubMed]
- Prays, J.; Ortiz-Villalon, C. Molecular landscape of thymic epithelial tumors. Semin. Diagn. Pathol. 2022, 39, 131–136. [Google Scholar] [CrossRef] [PubMed]
- Brierley, J.D.; Gospodarowicz, M.K.; Wittekind, C. (Eds.) TNM Classification of Malignant Tumours, 8th ed.; Oxford: Wiley-Blackwell, UK, 2016. [Google Scholar]
- Amin, M.B.; Edge, S.; Greene, F.; Byrd, D.R.; Brookland, R.K.; Washington, M.K.; Gershenwald, J.E.; Compton, C.C.; Hess, K.R.; Sullivan, D.C.; et al. (Eds.) AJCC Cancer Staging Manual, 8th ed.; Springer: New York, NY, USA, 2017. [Google Scholar]
- Bronner, I.F.; Quail, M.A.; Turner, D.J.; Swerdlow, H. Improved Protocols for Illumina Sequencing. Curr. Protoc. Hum. Genet. 2014, 80, 18.2.1–18.2.42. [Google Scholar] [CrossRef] [Green Version]
- Jennings, L.J.; Arcila, M.E.; Corless, C.; Kamel-Reid, S.; Lubin, I.M.; Pfeifer, J.; Temple-Smolkin, R.L.; Voelkerding, K.V.; Nikiforova, M.N. Guidelines for Validation of Next-Generation Sequencing-Based Oncology Panels: A Joint Consensus Recommendation of the Association for Molecular Pathology and College of American Pathologists. J. Mol. Diagn. 2017, 19, 341–365. [Google Scholar] [CrossRef] [Green Version]
- Sim, N.L.; Kumar, P.; Hu, J.; Henikoff, S.; Schneider, G.; Ng, P.C. SIFT web server: Predicting effects of amino acid substitutions on proteins. Nucleic Acids Res. 2012, 40, W452–W457. [Google Scholar] [CrossRef]
- Adzhubei, I.A.; Schmidt, S.; Peshkin, L.; Ramensky, V.E.; Gerasimova, A.; Bork, P.; Kondrashov, A.S.; Sunyaev, S.R. A method and server for predicting damaging missense mutations. Nat. Methods 2010, 7, 248–249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tate, J.G.; Bamford, S.; Jubb, H.C.; Sondka, Z.; Beare, D.M.; Bindal, N.; Boutselakis, H.; Cole, C.G.; Creatore, C.; Dawson, E.; et al. COSMIC: The Catalogue Of Somatic Mutations In Cancer. Nucleic Acids Res. 2019, 47, D941–D947. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Landrum, M.J.; Lee, J.M.; Riley, G.R.; Jang, W.; Rubinstein, W.S.; Church, D.M.; Maglott, D.R. ClinVar: Public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014, 42, D980–D985. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kopanos, C.; Tsiolkas, V.; Kouris, A.; Chapple, C.E.; Albarca Aguilera, M.; Meyer, R.; Massouras, A. VarSome: The human genomic variant search engine. Bioinformatics 2019, 35, 1978–1980. [Google Scholar] [CrossRef]
- Zhang, J.; Baran, J.; Cros, A.; Guberman, J.M.; Haider, S.; Hsu, J.; Liang, Y.; Rivkin, E.; Wang, J.; Whitty, B.; et al. International Cancer Genome Consortium Data Portal—A one-stop shop for cancer genomics data. Database 2011, 1, 2011. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karczewski, K.J.; Francioli, L.C.; Tiao, G.; Cummings, B.B.; Alfoldi, J.; Wang, Q.; Collins, R.L.; Laricchia, K.M.; Ganna, A.; Birnbaum, D.P.; et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020, 581, 434–443. [Google Scholar] [CrossRef] [PubMed]
- McNulty, S.N.; Parikh, B.A.; Duncavage, E.J.; Heusel, J.W.; Pfeifer, J.D. Optimization of Population Frequency Cutoffs for Filtering Common Germline Polymorphisms from Tumor-Only Next-Generation Sequencing Data. J. Mol. Diagn. 2019, 21, 903–912. [Google Scholar] [CrossRef]
- Cerami, E.; Gao, J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, B.A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; et al. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012, 2, 401–404. [Google Scholar] [CrossRef] [Green Version]
- Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal 2013, 6, pl1. [Google Scholar] [CrossRef] [Green Version]
- Bland, J.M.; Altman, D.G. Survival probabilities (the Kaplan-Meier method). BMJ 1998, 317, 1572. [Google Scholar] [CrossRef] [Green Version]
- Bland, J.M.; Altman, D.G. The logrank test. BMJ 2004, 328, 1073. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- MedCalc® Statistical Software, version 20.109; MedCalc Software Ltd.: Ostend, Belgium, 2022. Available online: https://www.medcalc.org(accessed on 26 May 2022).
- Basu, S.; Murphy, M.E. Genetic Modifiers of the p53 Pathway. Cold Spring Harb. Perspect. Med. 2016, 6, a026302. [Google Scholar] [CrossRef] [PubMed]
- Fleishman, S.J.; Schlessinger, J.; Ben-Tal, N. A putative molecular-activation switch in the transmembrane domain of erbB2. Proc. Natl. Acad. Sci. USA 2002, 99, 15937–15940. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krishna, B.M.; Chaudhary, S.; Panda, A.K.; Mishra, D.R.; Mishra, S.K. Her2 (Ile)655(Val) polymorphism and its association with breast cancer risk: An updated meta-analysis of case-control studies. Sci. Rep. 2018, 8, 1–19. [Google Scholar] [CrossRef] [PubMed]
- Radovich, M.; Pickering, C.R.; Felau, I.; Ha, G.; Zhang, H.; Jo, H.; Hoadley, K.A.; Anur, P.; Zhang, J.; McLellan, M.; et al. The Integrated Genomic Landscape of Thymic Epithelial Tumors. Cancer Cell 2018, 33, 244–258. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Thomas, A.; Lau, C.; Rajan, A.; Zhu, Y.; Killian, J.K.; Petrini, I.; Pham, T.; Morrow, B.; Zhong, X.; et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Sci. Rep. 2014, 4, 7336. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Enkner, F.; Pichlhofer, B.; Zaharie, A.T.; Krunic, M.; Holper, T.M.; Janik, S.; Moser, B.; Schlangen, K.; Neudert, B.; Walter, K.; et al. Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets. Pathol. Oncol. Res. 2017, 23, 551–564. [Google Scholar] [CrossRef] [Green Version]
- Petrini, I.; Rajan, A.; Pham, T.; Voeller, D.; Davis, S.; Gao, J.; Wang, Y.; Giaccone, G. Whole genome and transcriptome sequencing of a B3 thymoma. PLoS ONE 2013, 8, e60572. [Google Scholar] [CrossRef] [PubMed]
- Shitara, M.; Okuda, K.; Suzuki, A.; Tatematsu, T.; Hikosaka, Y.; Moriyama, S.; Sasaki, H.; Fujii, Y.; Yano, M. Genetic profiling of thymic carcinoma using targeted next-generation sequencing. Lung Cancer 2014, 86, 174–179. [Google Scholar] [CrossRef]
- Asao, T.; Fujiwara, Y.; Sunami, K.; Kitahara, S.; Goto, Y.; Kanda, S.; Horinouchi, H.; Nokihara, H.; Yamamoto, N.; Ichikawa, H.; et al. Medical treatment involving investigational drugs and genetic profile of thymic carcinoma. Lung Cancer 2016, 93, 77–81. [Google Scholar] [CrossRef]
- Sakane, T.; Sakamoto, Y.; Masaki, A.; Murase, T.; Okuda, K.; Nakanishi, R.; Inagaki, H. Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing. Clin. Lung Cancer 2021, 22, 92–99 e94. [Google Scholar] [CrossRef]
- Casini, B.; Sarti, D.; Gallo, E.; Alessandrini, G.; Cecere, F.; Pescarmona, E.; Facciolo, F.; Marino, M. Thymic carcinoma: Preliminary data of next generation sequencing analysis. Mediastinum 2018, 2, AB008. [Google Scholar] [CrossRef]
- Girard, N. Thymic tumors: Relevant molecular data in the clinic. J. Thorac. Oncol. 2010, 5, S291–S295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Girard, N.; Shen, R.; Guo, T.; Zakowski, M.F.; Heguy, A.; Riely, G.J.; Huang, J.; Lau, C.; Lash, A.E.; Ladanyi, M.; et al. Comprehensive genomic analysis reveals clinically relevant molecular distinctions between thymic carcinomas and thymomas. Clin. Cancer Res. 2009, 15, 6790–6799. [Google Scholar] [CrossRef] [Green Version]
- Kancha, R.K.; von Bubnoff, N.; Bartosch, N.; Peschel, C.; Engh, R.A.; Duyster, J. Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS ONE 2011, 6, e26760. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Robichaux, J.P.; Elamin, Y.Y.; Vijayan, R.S.K.; Nilsson, M.B.; Hu, L.; He, J.; Zhang, F.; Pisegna, M.; Poteete, A.; Sun, H.; et al. Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity. Cancer Cell 2019, 36, 444–457.e7. [Google Scholar] [CrossRef] [PubMed]
- Gebregiworgis, T.; Kano, Y.; St-Germain, J.; Radulovich, N.; Udaskin, M.L.; Mentes, A.; Huang, R.; Poon, B.P.K.; He, W.; Valencia-Sama, I.; et al. The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors. Nat. Commun. 2021, 12, 1–15. [Google Scholar] [CrossRef]
- Huang, L.; Guo, Z.; Wang, F.; Fu, L. KRAS mutation: From undruggable to druggable in cancer. Signal Transduct. Target. Ther. 2021, 6, 1–20. [Google Scholar] [CrossRef] [PubMed]
- Moreira, A.L.; Won, H.H.; McMillan, R.; Huang, J.; Riely, G.J.; Ladanyi, M.; Berger, M.F. Massively parallel sequencing identifies recurrent mutations in TP53 in thymic carcinoma associated with poor prognosis. J. Thorac. Oncol. 2015, 10, 373–380. [Google Scholar] [CrossRef] [Green Version]
- Xu, S.; Li, X.; Zhang, H.; Zu, L.; Yang, L.; Shi, T.; Zhu, S.; Lei, X.; Song, Z.; Chen, J. Frequent Genetic Alterations and Their Clinical Significance in Patients With Thymic Epithelial Tumors. Front. Oncol. 2021, 11, 667148. [Google Scholar] [CrossRef]
- Jiao, X.D.; Qin, B.D.; You, P.; Cai, J.; Zang, Y.S. The prognostic value of TP53 and its correlation with EGFR mutation in advanced non-small cell lung cancer, an analysis based on cBioPortal data base. Lung Cancer 2018, 123, 70–75. [Google Scholar] [CrossRef] [PubMed]
- Nakayama, M.; Oshima, M. Mutant p53 in colon cancer. J. Mol. Cell Biol. 2019, 11, 267–276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ungerleider, N.A.; Rao, S.G.; Shahbandi, A.; Yee, D.; Niu, T.; Frey, W.D.; Jackson, J.G. Breast cancer survival predicted by TP53 mutation status differs markedly depending on treatment. Breast Cancer Res. 2018, 20, 1–8. [Google Scholar] [CrossRef]
- Teroerde, M.; Nientiedt, C.; Duensing, A.; Hohenfellner, M.; Stenzinger, A.; Duensing, S. Revisiting the Role of p53 in Prostate Cancer. In Prostate Cancer; Bott, S.R.J., Ng, K.L., Eds.; Mayo Clinic: Brisbane, Australia, 2021. [Google Scholar]
- Song, Z.; Yu, X.; Zhang, Y. Rare frequency of gene variation and survival analysis in thymic epithelial tumors. Onco. Targets Ther. 2016, 9, 6337–6342. [Google Scholar] [CrossRef] [Green Version]
- Peric, J.; Samaradzic, N.; Trifunovic, V.S.; Tosic, N.; Stojsic, J.; Pavlovic, S.; Jovanovic, D. Genomic profiling of thymoma using a targeted high-throughput approach. Arch. Med. Sci. 2020. [Google Scholar] [CrossRef]
- Raymond, V.M.; Gray, S.W.; Roychowdhury, S.; Joffe, S.; Chinnaiyan, A.M.; Parsons, D.W.; Plon, S.E.; Clinical Sequencing Exploratory Research Consortium Tumor Working Group. Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. J. Natl. Cancer Inst. 2016, 108, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- DeLeonardis, K.; Hogan, L.; Cannistra, S.A.; Rangachari, D.; Tung, N. When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing? J. Oncol. Pract. 2019, 15, 465–473. [Google Scholar] [CrossRef]
- He, M.M.; Li, Q.; Yan, M.; Cao, H.; Hu, Y.; He, K.Y.; Cao, K.; Li, M.M.; Wang, K. Variant Interpretation for Cancer (VIC): A computational tool for assessing clinical impacts of somatic variants. Genom. Med. 2019, 11, 53. [Google Scholar] [CrossRef] [Green Version]
- Pahuja, K.B.; Nguyen, T.T.; Jaiswal, B.S.; Prabhash, K.; Thaker, T.M.; Senger, K.; Chaudhuri, S.; Kljavin, N.M.; Antony, A.; Phalke, S.; et al. Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. Cancer Cell 2018, 34, 792–806 e795. [Google Scholar] [CrossRef] [Green Version]
- Park, S.; Ahn, S.; Kim, D.G.; Kim, H.; Kang, S.Y.; Kim, K.M. High Frequency of Juxtamembrane Domain ERBB2 Mutation in Gastric Cancer. Cancer Genom. Proteom. 2022, 19, 105–112. [Google Scholar] [CrossRef]
- Pan, C.C.; Chen, P.C.; Wang, L.S.; Lee, J.Y.; Chiang, H. Expression of apoptosis-related markers and HER-2/neu in thymic epithelial tumours. Histopathology 2003, 43, 165–172. [Google Scholar] [CrossRef] [PubMed]
- Aisner, S.C.; Dahlberg, S.; Hameed, M.R.; Ettinger, D.S.; Schiller, J.H.; Johnson, D.H.; Aisner, J.; Loehrer, P.J. Epidermal growth factor receptor, C-kit, and Her2/neu immunostaining in advanced or recurrent thymic epithelial neoplasms staged according to the 2004 World Health Organization in patients treated with octreotide and prednisone: An Eastern Cooperative Oncology Group study. J. Thorac. Oncol. 2010, 5, 885–892. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mimae, T.; Tsuta, K.; Kondo, T.; Nitta, H.; Grogan, T.M.; Okada, M.; Asamura, H.; Tsuda, H. Protein expression and gene copy number changes of receptor tyrosine kinase in thymomas and thymic carcinomas. Ann. Oncol. 2012, 23, 3129–3137. [Google Scholar] [CrossRef] [PubMed]
- Roskoski, R., Jr. Structure and regulation of Kit protein-tyrosine kinase—The stem cell factor receptor. Biochem. Biophys. Res. Commun. 2005, 338, 1307–1315. [Google Scholar] [CrossRef]
- Yang, W.; Chen, S.; Cheng, X.; Xu, B.; Zeng, H.; Zou, J.; Su, C.; Chen, Z. Characteristics of genomic mutations and signaling pathway alterations in thymic epithelial tumors. Ann. Transl. Med. 2021, 9, 1659. [Google Scholar] [CrossRef]
- Nguyen, B.; Fong, C.; Luthra, A.; Smith, S.A.; DiNatale, R.G.; Nandakumar, S.; Walch, H.; Chatila, W.K.; Madupuri, R.; Kundra, R.; et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell 2022, 185, 563–575 e511. [Google Scholar] [CrossRef]
- Uhlenhaut, N.H.; Treier, M. Foxl2 function in ovarian development. Mol. Genet. Metab. 2006, 88, 225–234. [Google Scholar] [CrossRef]
- Leung, D.T.H.; Fuller, P.J.; Chu, S. Impact of FOXL2 mutations on signaling in ovarian granulosa cell tumors. Int. J. Biochem. Cell Biol. 2016, 72, 51–54. [Google Scholar] [CrossRef]
- Shah, S.P.; Kobel, M.; Senz, J.; Morin, R.D.; Clarke, B.A.; Wiegand, K.C.; Leung, G.; Zayed, A.; Mehl, E.; Kalloger, S.E.; et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N. Engl. J. Med. 2009, 360, 2719–2729. [Google Scholar] [CrossRef]
- Petrini, I.; Meltzer, P.S.; Kim, I.K.; Lucchi, M.; Park, K.S.; Fontanini, G.; Gao, J.; Zucali, P.A.; Calabrese, F.; Favaretto, A.; et al. A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat. Genet. 2014, 46, 844–849. [Google Scholar] [CrossRef] [Green Version]
- Higuchi, R.; Goto, T.; Hirotsu, Y.; Yokoyama, Y.; Nakagomi, T.; Otake, S.; Amemiya, K.; Oyama, T.; Mochizuki, H.; Omata, M. Primary Driver Mutations in GTF2I Specific to the Development of Thymomas. Cancers 2020, 12, 2032. [Google Scholar] [CrossRef] [PubMed]
- Yoh, K.; Nishiwaki, Y.; Ishii, G.; Goto, K.; Kubota, K.; Ohmatsu, H.; Niho, S.; Nagai, K.; Saijo, N. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008, 62, 316–320. [Google Scholar] [CrossRef] [PubMed]
- Walker, K.K.; Levine, A.J. Identification of a novel p53 functional domain that is necessary for efficient growth suppression. Proc. Natl. Acad. Sci. USA 1996, 93, 15335–15340. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sakamuro, D.; Sabbatini, P.; White, E.; Prendergast, G.C. The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 1997, 15, 887–898. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roth, J.; Koch, P.; Contente, A.; Dobbelstein, M. Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain. Oncogene 2000, 19, 1834–1842. [Google Scholar] [CrossRef] [Green Version]
- Toledo, F.; Lee, C.J.; Krummel, K.A.; Rodewald, L.W.; Liu, C.W.; Wahl, G.M. Mouse mutants reveal that putative protein interaction sites in the p53 proline-rich domain are dispensable for tumor suppression. Mol. Cell Biol. 2007, 27, 1425–1432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Barnoud, T.; Parris, J.L.D.; Murphy, M.E. Common genetic variants in the TP53 pathway and their impact on cancer. J. Mol. Cell Biol. 2019, 11, 578–585. [Google Scholar] [CrossRef]
- Marin, M.C.; Jost, C.A.; Brooks, L.A.; Irwin, M.S.; O’Nions, J.; Tidy, J.A.; James, N.; McGregor, J.M.; Harwood, C.A.; Yulug, I.G.; et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat. Genet. 2000, 25, 47–54. [Google Scholar] [CrossRef]
- Bergamaschi, D.; Gasco, M.; Hiller, L.; Sullivan, A.; Syed, N.; Trigiante, G.; Yulug, I.; Merlano, M.; Numico, G.; Comino, A.; et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell 2003, 3, 387–402. [Google Scholar] [CrossRef] [Green Version]
- Alaoui-Jamali, M.A.; Morand, G.B.; da Silva, S.D. ErbB polymorphisms: Insights and implications for response to targeted cancer therapeutics. Front. Genet. 2015, 6, 17. [Google Scholar] [CrossRef] [Green Version]
- Torres-Jasso, J.H.; Bustos-Carpinteyro, A.R.; Marin, M.E.; Santiago, E.; Leoner, C.; Flores-Luna, L.; Torres, J.; Sanchez-Lopez, J.Y. Analysis of the polymorphisms EGFR-r521K and ERBB2-I655V in Mexican patients with gastric cancer and premalignant gastric lesions. Rev. Investig. Clin. 2013, 65, 150–155. [Google Scholar] [PubMed]
- Loree, J.M.; Bailey, A.M.; Johnson, A.M.; Yu, Y.; Wu, W.; Bristow, C.A.; Davis, J.S.; Shaw, K.R.; Broaddus, R.; Banks, K.C.; et al. Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer. J. Natl. Cancer Inst. 2018, 110, 1409–1417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jo, U.H.; Han, S.G.; Seo, J.H.; Park, K.H.; Lee, J.W.; Lee, H.J.; Ryu, J.S.; Kim, Y.H. The genetic polymorphisms of HER-2 and the risk of lung cancer in a Korean population. BMC Cancer 2008, 8, 359. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Han, X.; Diao, L.; Xu, Y.; Xue, W.; Ouyang, T.; Li, J.; Wang, T.; Fan, Z.; Fan, T.; Lin, B.; et al. Association between the HER2 Ile655Val polymorphism and response to trastuzumab in women with operable primary breast cancer. Ann. Oncol. 2014, 25, 1158–1164. [Google Scholar] [CrossRef]
- Frank, B.; Hemminki, K.; Wirtenberger, M.; Bermejo, J.L.; Bugert, P.; Klaes, R.; Schmutzler, R.K.; Wappenschmidt, B.; Bartram, C.R.; Burwinkel, B. The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk. Carcinogenesis 2005, 26, 643–647. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brahmi, M.; Alberti, L.; Dufresne, A.; Ray-Coquard, I.; Cassier, P.; Meeus, P.; Decouvelaere, A.V.; Ranchere-Vince, D.; Blay, J.Y. KIT exon 10 variant (c.1621 A > C) single nucleotide polymorphism as predictor of GIST patient outcome. BMC Cancer 2015, 15, 780. [Google Scholar] [CrossRef] [Green Version]
- Minhas, S.; Bhalla, S.; Jauhri, M.; Ganvir, M.; Aggarwal, S. Clinico-Pathological Characteristics and Mutational Analysis of Gastrointestinal Stromal Tumors from India: A Single Institution Experience. Asian Pac. J. Cancer Prev. 2019, 20, 3051–3055. [Google Scholar] [CrossRef]
- Yim, E.; An, H.J.; Cho, U.; Kim, Y.; Kim, S.H.; Choi, Y.G.; Shim, B.Y. Two different KIT mutations may lead to different responses to imatinib in metastatic gastrointestinal stromal tumor. Korean J. Intern. Med. 2018, 33, 432–434. [Google Scholar] [CrossRef] [Green Version]
- Dufresne, A.; Alberti, L.; Brahmi, M.; Kabani, S.; Philippon, H.; Perol, D.; Blay, J.Y. Impact of KIT exon 10 M541L allelic variant on the response to imatinib in aggressive fibromatosis: Analysis of the desminib series by competitive allele specific Taqman PCR technology. BMC Cancer 2014, 14, 632. [Google Scholar] [CrossRef] [Green Version]
- Hoade, Y.; Metzgeroth, G.; Schwaab, J.; Reiter, A.; Cross, N.C.P. Routine Screening for KIT M541L Is Not Warranted in the Diagnostic Work-Up of Patients with Hypereosinophilia. Acta Haematol. 2018, 139, 71–73. [Google Scholar] [CrossRef] [Green Version]
- Schirosi, L.; Nannini, N.; Nicoli, D.; Cavazza, A.; Valli, R.; Buti, S.; Garagnani, L.; Sartori, G.; Calabrese, F.; Marchetti, A.; et al. Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. Ann. Oncol. 2012, 23, 2409–2414. [Google Scholar] [CrossRef] [PubMed]
- Engels, E.A. Epidemiology of thymoma and associated malignancies. J. Thorac. Oncol. 2010, 5, S260–S265. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Buti, S.; Donini, M.; Sergio, P.; Garagnani, L.; Schirosi, L.; Passalacqua, R.; Rossi, G. Impressive Response With Imatinib in a Heavily Pretreated Patient With Metastatic c-KIT Mutated Thymic Carcinoma. J. Clin. Oncol. 2011, 29, e803–e805. [Google Scholar] [CrossRef] [PubMed]
- Tiseo, M.; Damato, A.; Longo, L.; Barbieri, F.; Bertolini, F.; Stefani, A.; Migaldi, M.; Gnetti, L.; Camisa, R.; Bordi, P.; et al. Analysis of a panel of druggable gene mutations and of ALK and PD-L1 expression in a series of thymic epithelial tumors (TETs). Lung Cancer 2017, 104, 24–30. [Google Scholar] [CrossRef] [PubMed]
- Hirai, F.; Edagawa, M.; Shimamatsu, S.; Toyozawa, R.; Toyokawa, G.; Nosaki, K.; Yamaguchi, M.; Seto, T.; Twakenoyama, M.; Ichinose, Y. c-kit mutation-positive advanced thymic carcinoma successfully treated as a mediastinal gastrointestinal stromal tumor: A case report. Mol. Clin. Oncol. 2016, 4, 527–529. [Google Scholar] [CrossRef] [Green Version]
- Strobel, P.; Hartmann, M.; Jakob, A.; Mikesch, K.; Brink, I.; Dirnhofer, S.; Marx, A. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N. Engl. J. Med. 2004, 350, 2625–2626. [Google Scholar] [CrossRef]
- Dişel, U.; Öztuzcu, S.; Beşen, A.A.; Karadeniz, C.; Köse, F.; Sümbül, A.T.; Sezer, A.; Nursal, G.N.; Abalı, H.; Özyılkan, Ö. Promising efficacy of sorafenib in a relapsed thymic carcinoma with C-KIT exon 11 deletion mutation. Lung Cancer 2011, 71, 109–112. [Google Scholar] [CrossRef]
- Hagemann, I.S.; Govindan, R.; Javidan-Nejad, C.; Pfeifer, J.D.; Cottrell, C.E. Stabilization of Disease after Targeted Therapy in a Thymic Carcinoma with KIT Mutation Detected by Clinical Next-Generation Sequencing. J. Thorac. Oncol. 2014, 9, e12–e16. [Google Scholar] [CrossRef] [Green Version]
- Lim, S.H.; Lee, J.-Y.; Sun, J.-M.; Kim, K.-M.; Ahn, J.S.; Ahn, M.-J.; Park, K. A new KIT gene mutation in thymic cancer and a promising response to imatinib. J. Thorac. Oncol. 2013, 8, e91–e92. [Google Scholar] [CrossRef] [Green Version]
- Catania, C.; Conforti, F.; Spitaleri, G.; Barberis, M.; Preda, L.; Noberasco, C.; Manzotti, M.; Toffalorio, F.; De Pas, T.; Lazzari, C.; et al. Antitumor activity of sorafenib and imatinib in a patient with thymic carcinoma harboring c-KIT exon 13 missense mutation K642E. OncoTargets Therapy 2014, 7, 697–702. [Google Scholar] [CrossRef] [Green Version]
- Bisagni, G.; Rossi, G.; Cavazza, A.; Sartori, G.; Gardini, G.; Boni, C. Long Lasting Response to the Multikinase Inhibitor Bay 43-9006 (Sorafenib) in a Heavily Pretreated Metastatic Thymic Carcinoma. J. Thorac. Oncol. 2009, 4, 773–775. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pagano, M.; Sierra, N.M.A.; Panebianco, M.; Rossi, G.; Gnoni, R.; Bisagni, G.; Boni, C. Sorafenib efficacy in thymic carcinomas seems not to require c-KIT or PDGFR-alpha mutations. Anticancer Res. 2014, 34, 5105–5110. [Google Scholar] [PubMed]
Characteristics | Thymomas | N (%) | Thymic Carcinomas * | N (%) | Total |
---|---|---|---|---|---|
Number of cases | All | 19 (36%) | All | 34 (64%) | 53 (100%) |
Median age (range) in years | 57 (22–87) | 57 (30–80) | 57 (22–87) | ||
Gender | Male | 13 (25%) | Male | 24 (45%) | 37 (70%) |
Female | 6 (11%) | Female | 10 (19%) | 16 (30%) | |
Histology (WHO 2021) | A | 1 (2%) | Squamous cell carcinoma ** | 23 (43%) | |
AB | 4 (8%) | Basaloid carcinoma | 1 (2%) | ||
B2 | 5 (9%) | Adenocarcinoma | 1 (2%) | ||
B3 | 1 (2%) | Mucoepidermoid carcinoma | 1 (2%) | ||
Combined B2B3 | 5 (9%) | NUT carcinoma | 1 (2%) | ||
MTLS | 3 (6%) | LCNEC | 6 (11%) | ||
Carcinoma, NOS | 1 (2%) | ||||
Stage (TNM) | I | 12 (23%) | I | 4 (8%) | |
II | 0 (0%) | II | 0 (0%) | ||
III (A + B) | 1 (2%) | III (A + B) | 3 (6%) | ||
IV (A + B) | 4 (8%) | IV (A + B) | 9 (17%) | ||
n/a | 2 (4%) | n/a | 18 (34%) | ||
Myasthenia gravis | Yes | 5 (9%) | Yes | 0 (0%) | |
No | 14 (26%) | No | 34 (64%) | ||
Adjuvant treatment | None | 7 (13%) | None | 2 (4%) | |
RTH | 8 (15%) | RTH | 5 (9%) | ||
CHTH | 1 (2%) | CHTH | 5 (9%) | ||
RTH + CHTH | 2 (4%) | RTH + CHTH | 13 (25%) | ||
n/a | 1 (2%) | n/a | 9 (17%) |
Sample ID | TET Histology | TET Subtype | Gene | HGVSC | HGVSP | Variant Position | Allele Frequency (GnomAD) | dbSNP | COSMIC ID | Mutation Type | Clinical Significance (VarSome) | Variant Read Frequency | Coverage [Reads] |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
#29 | TC | LNEC | TP53 | c.461G>T | p.(Gly154Val) | chr17:7578469 | n/a | rs762846821 | COSM6815 | missense | likely pathogenic | 0.82 | 3107 |
#19 | TC | SQCC | TP53 | c.473G>C | p.(Arg158Pro) | chr17:7578457 | n/a | rs587782144 | COSM43615 | missense | pathogenic | 0.45 | 4832 |
#31 | TC | ADC | TP53 | c.581T>A | p.(Leu194His) | chr17:7578268 | 0.000 | rs1057519998 | COSM43623 | missense | pathogenic | 0.21 | 4354 |
#8 | TC | SQCC | TP53 | c.799_802del | p.(Arg267ThrfsTer77) | chr17:7577136 | n/a | n/a | n/a | frameshift | pathogenic | 0.80 | 2506 |
#34 | TC | NOS | TP53 | c.817C>T | p.(Arg273Cys) | chr17:7577121 | 0.000 | rs121913343 | COSM10659 | missense | pathogenic | 0.73 | 1929 |
#3 | TC | SQCC | TP53 | c.916C>T | p.(Arg306Ter) | chr17:7577022 | 0.000 | rs121913344 | COSM10663 | stop gain | pathogenic | 0.44 | 3338 |
#5 | TC | SQCC | TP53 | c.916C>T | p.(Arg306Ter) | chr17:7577022 | 0.000 | rs121913344 | COSM10663 | stop gain | pathogenic | 0.38 | 2395 |
#26 | TC | LNEC | TP53 | c.949C>T | p.(Gln317Ter) | chr17:7576897 | n/a | rs764735889 | COSM10786 | stop gain | pathogenic | 0.90 | 19,414 |
#50 | TM | B2B3 | ERBB2 | c.2109C>G | p.(Ser703Arg) | chr17:37879814 | n/a | n/a | n/a | missense | uncertain | 0.10 | 888 |
#18 | TC | SQCC | ERBB2 | c.2317G>A | p.(Val773Met) | chr17:37880988 | 0.000015 | rs772054394 | COSM5731177 | missense | pathogenic | 0.07 | 2483 |
#30 | TC | Basaloid | KIT | c.1727T>C | p.(Leu576Pro) | chr4:55593661 | n/a | rs121913513 | COSM1290 | missense | pathogenic | 0.41 | 740 |
#49 | TM | B2B3 | KIT | c.2068A>G | p.(Ile690Val) | chr4:55595578 | 0.000009 | rs924104591 | n/a | missense | uncertain | 0.53 | 684 |
#34 | TC | NOS | KRAS | c.182A>T | p.(Gln61Leu) | chr12:25380276 | 0.000 | rs121913240 | COSM553 | missense | pathogenic | 0.87 | 38,464 |
#52 | TM | MTLS | FOXL2 | c.469C>T | p.(Pro157Ser) | chr3:138665096 | 0.000 | rs758370933 | n/a | missense | uncertain | 0.06 | 4905 |
Gene | HGVSC | HGVSP | Variant Position | Variant Frequency in TETs | Allele Frequency (GnomAD) | dbSNP | COSMIC ID | Mutation Type | Clinical Significance (VarSome) | Variant Read Frequency | Median Coverage [Reads] |
---|---|---|---|---|---|---|---|---|---|---|---|
TP53 | c.215C>G | p.(Pro72Arg) | chr17:7579472 | 50/53 (94%) | 0.7366 | rs1042522 | COSM250061 | missense | benign | 0.19–1.00 | 17,854 |
ERBB2 | c.1963A>G | p.(Ile655Val) | chr17:37879588 | 21/53 (40%) | 0.2405 | rs1136201 | COSM4000121 | missense | benign | 0.23–1.00 | 2600 |
ERBB2 | c.1960A>G | p.(Ile654Val) | chr17:37879585 | 1/53 (2%) | 0.0081 | rs1801201 | COSM6854579 | missense | benign | 0.59 | 2718 |
KIT | c.1621A>C | p.(Met541Leu) | chr4:55593464 | 5/53 (9%) | 0.0969 | rs3822214 | COSM28026 | missense | benign | 0.45–0.53 | 2198 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Szpechcinski, A.; Szolkowska, M.; Winiarski, S.; Lechowicz, U.; Wisniewski, P.; Knetki-Wroblewska, M. Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas. Cancers 2022, 14, 3388. https://doi.org/10.3390/cancers14143388
Szpechcinski A, Szolkowska M, Winiarski S, Lechowicz U, Wisniewski P, Knetki-Wroblewska M. Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas. Cancers. 2022; 14(14):3388. https://doi.org/10.3390/cancers14143388
Chicago/Turabian StyleSzpechcinski, Adam, Malgorzata Szolkowska, Sebastian Winiarski, Urszula Lechowicz, Piotr Wisniewski, and Magdalena Knetki-Wroblewska. 2022. "Targeted Next-Generation Sequencing of Thymic Epithelial Tumours Revealed Pathogenic Variants in KIT, ERBB2, KRAS, and TP53 in 30% of Thymic Carcinomas" Cancers 14, no. 14: 3388. https://doi.org/10.3390/cancers14143388