Clinicopathological and Prognostic Significance of the 
EML4-ALK Translocation and IGFR1, TTF1, Napsin A 
Expression in Patients with Lung Adenocarcinoma

Akyurek, Nalan; MEMİŞ, Leyla; BULUTAY, PINAR

doi:10.5146/tjpath.2020.01503

Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma

Pınar BULUTAY, (Koç Üniversitesi Hastanesi, Patoloji Anabilim Dalı, İstanbul, Türkiye)

Nalan AKYÜREK, (Gazi Üniversitesi Hastanesi, Ankara, Türkiye)

Leyla MEMİŞ (Gazi Üniversitesi Hastanesi, Ankara, Türkiye)

Türk Patoloji Dergisi

2 0

Yıl: 2021 Cilt: 37 Sayı: 1 Sayfa Aralığı: 7 - 17 Metin Dili: İngilizce DOI: 10.5146/tjpath.2020.01503 İndeks Tarihi: 14-06-2022

Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma

Öz:

Objective: Patients with lung adenocarcinoma who harbor ALK gene rearrangements can demonstrate significant clinical benefit with ALK tyrosine kinase inhibitors. Insulin-like growth factor receptor 1 (IGFR1) is a cellular membrane receptor that is overexpressed in many tumors. It plays an important role in cancer progression and is associated with increased postoperative recurrence and poorer disease-free survival. The aim of this study was to determine the EML4-ALK mutation and IGFR1 expression in lung adenocarcinoma and analyze their prognostic value. Material and Method: In this study, we analyzed the EML4-ALK mutation using the FISH and IHC techniques in 251 lung adenocarcinoma (203 primary resections, 48 metastasectomies) cases. Correlative analyses were performed between the EML4-ALK mutation, the IGFR1, TTF1, and NapsinA expression, and the clinicopathologic factors in lung adenocarcinomas. Results: The EML4-ALK mutation was observed in 3.8% of the cases and it was associated with the solid pattern, signet ring cell morphology, and larger tumor size. IGFR1 expression was identified in 49% of the cases and most of the ALK-mutated cases were also expressing the IGFR1 protein (66%). IGFR1 expression frequency was increased in metastasectomy specimens. Conclusion: A solid signet-ring cell pattern or mucinous cribriform pattern was present at least focally in all ALK-positive tumors, consistently with the literature. In addition, IGFR1 expression levels showed an increase in the EML4-ALK-mutated cases in our series, but the clinical significance of this finding should be supported by larger series and survival analysis. Our findings show that IGFR1 expression may be useful as a poor prognostic marker in patients with lung adenocarcinoma.

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1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.
2. Didkowska J, Wojciechowska U, Mańczuk M, Lobaszewski J. Lung cancer epidemiology: Contemporary and future challenges worldwide. Ann Transl Med. 2016;4:150.
3. Isaka T, Nakayama H, Ito H, Yokose T, Yamada K, Masuda M. Impact of the epidermal growth factor receptor mutation status on the prognosis of recurrent adenocarcinoma of the lung after curative surgery. BMC Cancer. 2018;18:959.
4. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara SI, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-6.
5. Solomon B, Varella-Garcia M, Camidge DR. ALK gene rearrangements: A new therapeutic target in a molecularly defined subset of non-small cell lung cancer. J Thorac Oncol. 2009;4:1450-4.
6. Patel SP, Pakkala S, Pennell NA, Reckamp KL, Lanzalone S, Polli A, Jamal T, Robert Vizcarrondo F. Phase Ib Study of Crizotinib Plus Pembrolizumab in Patients with Previously Untreated Advanced Non Small Cell Lung Cancer with ALK Translocation. Oncologist. 2020;25:562-e1012.
7. Fan J, Fong T, Xia Z, Zhang J, Luo P. The efficacy and safety of ALK inhibitors in the treatment of ALK-positive non-small cell lung cancer: A network meta-analysis. Cancer Med. 2018;7:4993- 5005.
8. Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, Colasacco C, Dacic S, Hirsch F, Kerr K, Kwiatkowski D, Ladanyi M, Nowak J, Sholl L, Temple S, Solomon B, Souter L, Thunnissen E, Tsao M, Ventura C, Wynes M, Yatabe Y. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the college of American pathologists, the international association for the study of lung cancer, and the association for molecular pathology. Arch Pathol Lab Med. 2018;142:321-46.
9. Tian P, Liu Y, Zeng H, Tang Y, Lizaso A, Ye J Shao, Lin, Li Y. Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes. J Cancer Res Clin Oncol. 2020;146:935-44.
10. Zhao F, Xu M, Lei H, Zhou Z, Wang L, Li P ZJ, Hu P. Clinicopathological characteristics of patients with non-smallcell lung cancer who harbor EML4-ALK fusion gene: A metaanalysis. PLoS One. 2015;10:e0117333.
11. Khandwala HM, Mccutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev. 2000;21:215-44.
12. Nakagawa M, Uramoto H, Shimokawa H, Onitsuka T, Hanagiri T, Tanaka F. Insulin-like growth factor receptor-1 expression predicts postoperative recurrence in adenocarcinoma of the lung. Exp Ther Med. 2011;2:585-90.
13. Liang C, Zhang N, Tan Q, Liu S, Luo R, Wang Y Shi, Yuankai Han X. CT-707 overcomes resistance of crizotinib through activating PDPK1- AKT1 pathway by targeting FAK. Current Cancer Drug Targets. 2018;19:655-65.
14. Cui C, Hu P, Jiang J, Kong F, Luo H, Zhao Q. An UPLC-MS/MS method to determine CT-707 and its two metabolites in plasma of ALK-positive advanced non-small cell lung cancer patients. J Pharm Biomed Anal. 2018;153:1-8.
15. Kadota K, Nitadori JI, Sarkaria IS, Sima CS, Jia X, Yoshizawa A, Rusch VW, Travis WD, Adusumilli PS. Thyroid transcription factor-1 expression is an independent predictor of recurrence and correlates with the IASLC/ATS/ERS histologic classification in patients with stage i lung adenocarcinoma. Cancer. 2013;119:931- 8.
16. Dziadziuszko R, Merrick DT, Witta SE, Mendoza AD, Szostakiewicz B, Szymanowska ARW, Dziadziuszko K, Jassem J, Bunn PA, Varella GM, Hirsch FR. Insulin-like growth factor receptor 1 (IGF1R) gene copy number is associated with survival in operable non-small-cell lung cancer: A comparison between IGF1R fluorescent in situ hybridization, protein expression, and mRNA expression. J Clin Oncol. 2010;28:2174-80.
17. Travis WD, Brambilla E, Van Schil P, Scagliotti G V., Huber RM, Sculier JP Vansteenkiste J, Nicholson AG. Paradigm shifts in lung cancer as defined in the new IASLC/ATS/ERS lung adenocarcinoma classification. Eur Respir J. 2011;38:239-43.
18. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Ignacio W. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances since the 2004 Classification. J Thorac Oncol. 2015;10:1243-60.
19. Hochmair M, Weinlinger C, Schwab S, Naber J, Setinek U, Krenbek D Urban, Matthias H, Fabikan H, Watzka S, Koger R, Fazekas A, Bitterlich E, Valipour A, Burghuber OC. Treatment of ALK -rearranged non-small-cell lung cancer with brigatinib as second or later lines: Real-world observations from a single institution. Anti-Cancer Drugs 2019;30:740-4.
20. Liu Y, Wu S, Shi X, Liang Z, Zeng X. ALK detection in lung cancer: Identification of atypical and cryptic ALK rearrangements using an optimal algorithm. J Cancer Res Clin Oncol. 2020;146:1307- 20.
21. Zhao R, Zhang J, Han Y, Shao J, Zhu L, Xiang C, Zhang Q, Teng H, Qin G, Zhao L, Ye M, Zhao J, Ding W, Ye M, Zhao J, Ding W. Clinicopathological features of ALK expression in 9889 cases of non-small-cell lung cancer and genomic rearrangements identified by capture-based next-generation sequencing: A Chinese retrospective analysis. Mol Diagn Ther. 2019;23:395-405.
22. Kometani T, Sugio K, Osoegawa A, Seto T, Ichinose Y. Clinicopathological features of younger (aged ≤ 50 years) lung adenocarcinoma patients harboring the EML4-ALK fusion gene. Thorac Cancer. 2018;9:563-70.
23. Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, Solomon B, Stubbs H, Admane S, McDermott U, Settleman J, Kobayashi S, Mark EJ, Rodig SJ, Chirieac LR, Kwak EL, Lynch TJ, Iafrate AJ. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-53.
24. Shi J, Gu W, Zhao Y, Zhu J, Jiang G, Bao M, Shi J. Clinicopathological and prognostic significance of EML4- ALK rearrangement in patients with surgically resected lung adenocarcinoma: A propensity score matching study. Cancer Manag Res. 2020;12:589-98.
25. Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, Stubbs H, Law K, Lindeman N, Mark E, Janne PA, Lynch T, Johnson BE, Iafrate AJ, Chirieac LR. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009;15:5216-23.
26. Yoshida A, Tsuta K, Nakamura H, Kohno T, Takahashi F, Asamura H Sekine, Ikuo, Fukayama M, Shibata T, Furuta K, Tsuda H. Comprehensive histologic analysis of ALK-rearranged lung carcinomas. Am J Surg Pathol. 2011;35:1226-34.
27. Adachi Y, Li R, Yamamoto H, Min Y, Piao W, Wang Y, Imsumran A, Li H, Arimura Y, Lee, CT, Imai K, Carbone DP, Shinomura Y. Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin. Carcinogenesis. 2009;30:1305-13.
28. Lewis DA, Travers JB, Somani AK, Spandau DF. The IGF-1/IGF1R signaling axis in the skin: A new role for the dermis in agingassociated skin cancer. Oncogene. 2010;29:1475-85.
29. Wang DD, Chen Y, Chen ZB, Yan FJ, Dai XY, Ying MD, Cao J, Ma J, Luo P, Han Y, Peng Y, Sun Y, Zhang H, He Q, Yang B, Zhu H. CT-707, a novel FAK inhibitor, synergizes with cabozantinib to suppress hepatocellular carcinoma by blocking cabozantinibinduced FAK activation. Mol Cancer Ther. 2016;15:2916-25.
30. Taliaferro-Smith LT, Oberlick E, Liu T, McGlothen T, Alcaide T, Tobin R, Donnelly S, Commander R, Kline E, Nagaraju G, Havel L, Marcus A, Nahta R, O’Regan R. FAK activation is required for IGF1R-mediated regulation of EMT, migration, and invasion in mesenchymal triple negative breast cancer cells. Oncotarget. 2015;6:4757-72.
31. Liu B, Shi SS, Wang X, Xu Y, Zhng XH, Yu H, Lu Z, Wang D, Zhou J. Relevance of molecular alterations in histopathologic subtyping of lung adenocarcinoma based on 2011 international multidisciplinary lung adenocarcinoma classification. Zhonghua Bing Li Xue Za Zhi. 2012;41:505-10.
32. Zhang P, Han YP, Huang L, Li Q, Ma DL. Value of napsin A and thyroid transcription factor-1 in the identification of primary lung adenocarcinoma. Oncol Lett. 2010;1:899-903.
33. Inamura K, Takeuchi K, Togashi Y, Hatano S, Ninomiya H, Motoi N, Mun M, Sakao Y, Okumura S, Nakagawa K, Soda M, Lim Y, Mano H, Ishikawa Y. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol. 2009;22:508-15.
34. Yatabe Y, Kosaka T, Takahashi T, Mitsudomi T. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol. 2005;29:633-9.

APA	BULUTAY P, Akyurek N, MEMİŞ L (2021). Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. , 7 - 17. 10.5146/tjpath.2020.01503
Chicago	BULUTAY PINAR,Akyurek Nalan,MEMİŞ Leyla Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. (2021): 7 - 17. 10.5146/tjpath.2020.01503
MLA	BULUTAY PINAR,Akyurek Nalan,MEMİŞ Leyla Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. , 2021, ss.7 - 17. 10.5146/tjpath.2020.01503
AMA	BULUTAY P,Akyurek N,MEMİŞ L Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. . 2021; 7 - 17. 10.5146/tjpath.2020.01503
Vancouver	BULUTAY P,Akyurek N,MEMİŞ L Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. . 2021; 7 - 17. 10.5146/tjpath.2020.01503
IEEE	BULUTAY P,Akyurek N,MEMİŞ L "Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma." , ss.7 - 17, 2021. 10.5146/tjpath.2020.01503
ISNAD	BULUTAY, PINAR vd. "Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma". (2021), 7-17. https://doi.org/10.5146/tjpath.2020.01503

APA	BULUTAY P, Akyurek N, MEMİŞ L (2021). Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. Türk Patoloji Dergisi, 37(1), 7 - 17. 10.5146/tjpath.2020.01503
Chicago	BULUTAY PINAR,Akyurek Nalan,MEMİŞ Leyla Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. Türk Patoloji Dergisi 37, no.1 (2021): 7 - 17. 10.5146/tjpath.2020.01503
MLA	BULUTAY PINAR,Akyurek Nalan,MEMİŞ Leyla Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. Türk Patoloji Dergisi, vol.37, no.1, 2021, ss.7 - 17. 10.5146/tjpath.2020.01503
AMA	BULUTAY P,Akyurek N,MEMİŞ L Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. Türk Patoloji Dergisi. 2021; 37(1): 7 - 17. 10.5146/tjpath.2020.01503
Vancouver	BULUTAY P,Akyurek N,MEMİŞ L Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma. Türk Patoloji Dergisi. 2021; 37(1): 7 - 17. 10.5146/tjpath.2020.01503
IEEE	BULUTAY P,Akyurek N,MEMİŞ L "Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma." Türk Patoloji Dergisi, 37, ss.7 - 17, 2021. 10.5146/tjpath.2020.01503
ISNAD	BULUTAY, PINAR vd. "Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma". Türk Patoloji Dergisi 37/1 (2021), 7-17. https://doi.org/10.5146/tjpath.2020.01503