Detection of ALK/ROS1/RET Fusion Genes in Non-small Cell Lung Cancer and Their Correlation with Clinical Features_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

LIUGuang-yuan , ZHUJiang , WENYan ,  HEJin-tao

Department of Pulmonary Neoplasm, Sichuan Cancer Hospital, Chengdu 610041, P. R. China;

Corresponding author：

HEJin-tao, Email: hjtabc3@163.com

Keywords：

Non-small cell lung cancer; Anaplastic lymphoma kinase; ROS1 gene; RET gene; Gene rearrangement

DOI：

10.7507/1007-4848.20140147

Video：

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Objective To detect the frequency of anaplastic lymphoma kinase (ALK), ROS1 and RET fusion genes in non-small cell lung cancer (NSCLC) patients in Sichuan, and analyze their correlation with clinical features of NSCLC. Methods Reverse transcription-polymerase chain reaction (RT-PCR) was performed to examine gene rearrangement of ALK, ROS1 and RET fusion genes in 310 NSCLC patients who were admitted in Department of Pulmonary Neoplasm of Sichuan Cancer Hospital from March 2009 to March 2012. There were 234 male and 76 female patients with their median age of 60 years (range, 29 to 77 years). There were 164 patients with a smoking history. Histological types included adeno-carcinoma (AC) in 142 patients, squamous cell carcinoma (SCC) in 138 patients, adenosquamous carcinoma in 10 patients, and other types in 20 patients. Patients, gender, age, smoking history, histological types and TNM staging were also collected. Correlations between fusion genes and clinical features were analyzed. Results Among the 310 patient:15 patients with ALK fusion genes were identified (EML4-ALK) with a positive rate of 4.84%, including 14 patients with AC and 1 patient with SCC. ALK fusion genes were more common in patients under 60 years, without a smoking history, and with AC (P < 0.05). ALK fusion genes were not significantly correlated with gender or histodifferentiation. One patient with ROS1 fusion genes (CD74-ROS1) was identified with a positive rate of 0.32%, who was AC patients. Two patients with RET fusion genes (KIF5B-RET) were identified with a positive rate of 0.64%, both of whom were AC patients. Conclusions Gene rearran-gement rates of ALK, ROS1 and RET in NSCLC patients in Sichuan are 4.84%, 0.32% and 0.64% respectively. Patients with negative gene mutation of epithelial growth factor receptor (EGFR), AC, younger age, without a smoking history or with a light smoking history are more common to have ALK gene rearrangement. Gene rearrangement rates of ROS1 and RET are low, and their clinical significance needs more research.

Citation： LIUGuang-yuan, ZHUJiang, WENYan, HEJin-tao. Detection of ALK/ROS1/RET Fusion Genes in Non-small Cell Lung Cancer and Their Correlation with Clinical Features. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2014, 21(4): 522-525. doi: 10.7507/1007-4848.20140147 Copy

1.	Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin, 2007, 57 (1):43-66.
2.	Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res, 2008, 14 (13):4275-4283.
3.	Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol, 2009, 27 (26):4247-4253.
4.	Lin E, Li L, Guan YH, et al. Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res, 2009, 7 (9):1466-1476.
5.	Martelli MP, Sozzi G, Hernandez L, et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol, 2009, 174 (2):661-670.
6.	Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from"never smokers. and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc Natl Acad Sci U S A, 2004, 101 (36):13306-13311.
7.	Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362 (25):2380-2388.
8.	Morris SW, Naeve C, Mathew P, et al. ALK, the chromosome 2 gene locus altered by the t (2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene, 1997, 14 (18):2175-2188.
9.	Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 2007, 448 (7153):561-566.
10.	Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer, 2009, 115 (8):1723-1733.
11.	Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 2010, 363 (18):1693-1703.
12.	Yi ES, Boland JM, Maleszewski JJ, et al. Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma:IHC score algorithm for FISH. J Thorac Oncol, 2011, 6 (3):459-465.
13.	Ou SH, Bartlett CH, Mino-Kenudson M, et al. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer:a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist, 2012, 17 (11):1351-1375.
14.	Sasaki T, Rodig SJ, Chirieacc LR, et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer, 2010, 46 (10):1773-1780.
15.	Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol, 2011, 12 (2):175-180.
16.	Bonner AE, Lemon WJ, Devereux TR, et al. Molecular profiling of mouse lung tumors:association with tumor progression, lung development, and human lung adenocarcinomas. Oncogene, 2004, 23 (5):1166-1176.
17.	Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbo-uring ALK gene rearrangement:a retrospective analysis. Lancet Oncol, 2011, 12 (11):1004-1012.
18.	Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol, 2012, 30 (8):863-870.
19.	Birchmeier C, Sharma S, Wigler M. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A, 1987, 84 (24):9270-9274.
20.	Rikova K, Guo A, Zeng Q, et al. Global survey of phospho tyrosine signaling identifies oncogenic kinases in lung cancer. Cell, 2007, 131 (6):1190-1203.
21.	Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med, 2012, 18 (3):382-384.
22.	Kuo YW, Wu SG, Ho CC, et al. Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol, 2010, 5 (12):2039-2040.
23.	Shaw AT, Camidge DR, Engelman JA, et al. Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. J Clin Oncol, 2012, 30 (15 Suppl):7508. 24 Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med, 2012, 18 (3):378-381.
24.	Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med, 2012, 18(3): 378-381.
25.	Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med, 2012, 18 (3):375-377.

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin, 2007, 57 (1):43-66.
2. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res, 2008, 14 (13):4275-4283.
3. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol, 2009, 27 (26):4247-4253.
4. Lin E, Li L, Guan YH, et al. Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res, 2009, 7 (9):1466-1476.
5. Martelli MP, Sozzi G, Hernandez L, et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol, 2009, 174 (2):661-670.
6. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from"never smokers. and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc Natl Acad Sci U S A, 2004, 101 (36):13306-13311.
7. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med, 2010, 362 (25):2380-2388.
8. Morris SW, Naeve C, Mathew P, et al. ALK, the chromosome 2 gene locus altered by the t (2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene, 1997, 14 (18):2175-2188.
9. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 2007, 448 (7153):561-566.
10. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer, 2009, 115 (8):1723-1733.
11. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 2010, 363 (18):1693-1703.
12. Yi ES, Boland JM, Maleszewski JJ, et al. Correlation of IHC and FISH for ALK gene rearrangement in non-small cell lung carcinoma:IHC score algorithm for FISH. J Thorac Oncol, 2011, 6 (3):459-465.
13. Ou SH, Bartlett CH, Mino-Kenudson M, et al. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer:a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist, 2012, 17 (11):1351-1375.
14. Sasaki T, Rodig SJ, Chirieacc LR, et al. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer, 2010, 46 (10):1773-1780.
15. Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol, 2011, 12 (2):175-180.
16. Bonner AE, Lemon WJ, Devereux TR, et al. Molecular profiling of mouse lung tumors:association with tumor progression, lung development, and human lung adenocarcinomas. Oncogene, 2004, 23 (5):1166-1176.
17. Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbo-uring ALK gene rearrangement:a retrospective analysis. Lancet Oncol, 2011, 12 (11):1004-1012.
18. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol, 2012, 30 (8):863-870.
19. Birchmeier C, Sharma S, Wigler M. Expression and rearrangement of the ROS1 gene in human glioblastoma cells. Proc Natl Acad Sci U S A, 1987, 84 (24):9270-9274.
20. Rikova K, Guo A, Zeng Q, et al. Global survey of phospho tyrosine signaling identifies oncogenic kinases in lung cancer. Cell, 2007, 131 (6):1190-1203.
21. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med, 2012, 18 (3):382-384.
22. Kuo YW, Wu SG, Ho CC, et al. Good response to gefitinib in lung adenocarcinoma harboring coexisting EML4-ALK fusion gene and EGFR mutation. J Thorac Oncol, 2010, 5 (12):2039-2040.
23. Shaw AT, Camidge DR, Engelman JA, et al. Clinical activity of crizotinib in advanced non-small cell lung cancer (NSCLC) harboring ROS1 gene rearrangement. J Clin Oncol, 2012, 30 (15 Suppl):7508. 24 Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med, 2012, 18 (3):378-381.
24. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med, 2012, 18(3): 378-381.
25. Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med, 2012, 18 (3):375-377.

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Detection of ALK/ROS1/RET Fusion Genes in Non-small Cell Lung Cancer and Their Correlation with Clinical Features

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