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. 2020 Feb 19;1(1):100015. doi: 10.1016/j.jtocrr.2020.100015

Catalog of 5’ Fusion Partners in ALK-positive NSCLC Circa 2020

Sai-Hong Ignatius Ou a,∗, Viola W Zhu a, Misako Nagasaka b,c
PMCID: PMC8474466  PMID: 34589917

Abstract

Since the discovery of anaplastic lymphoma kinase fusion-positive (ALK+) NSCLC in 2007, the methods to detect ALK+ NSCLC have evolved and expanded from fluorescence in situ hybridization and immunohistochemistry to next-generation DNA sequencing, targeted RNA sequencing, and whole transcriptome sequencing. As such, the deep sequencing methods have resulted in the expansion of distinct fusion partners identified in ALK+ NSCLC to 90 (one variant PLEKHM2-ALK is found in small cell lung cancer but included in this catalog) by the end of January 2020; about 65 of them (since 2018) and most of the recent novel fusion partners were reported from China. Thirty-four of the distinct fusion partners are located on the short arm of chromosome 2; 28 of these 34 fusion partners are located on 2p21-25, in which ALK is located on 2p23.2-p23.1. Many of these new ALK+ NSCLC fusion variants have responded to ALK tyrosine kinase inhibitors (TKIs). Several of these novel ALK fusion variants were identified as being resistant to EGFR TKIs or as dual 3’ALK fusions. In addition, at least 28 intergenic ALK rearrangements have also been reported, with three of them reported as responding to crizotinib. This review aims to serve as a central source of reference of fusion partners in ALK+ NSCLC for clinicians and scientists. We aim to update and improve the list going forward.

Keywords: ALK fusion partners, Next-generation sequencing, ALK+ NSCLC, Whole transcriptome sequencing

Introduction

Since the discovery of anaplastic lymphoma kinase fusion-positive (ALK+) NSCLC (EML4-ALK, TPF-ALK) in 2007,1,2 there has been a rapid development of ALK tyrosine kinase inhibitors (TKIs) to treat ALK+ NSCLC with five ALK TKIs approved in the United States (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) by 2018. At the same time, the detection of ALK+ NSCLC has expanded and shifted from the original methods of fluorescence in situ hybridization and immunochemistry (IHC) to next-generation sequencing (NGS), targeted RNA seqencing, and even whole transcriptome sequencing being offered by commercial sequencing companies. Targeted RNA sequencing and whole transcriptome sequencing have been used to supplement DNA NGS to detect even rare actionable driver mutations such as NTRK and NRG1.3,4 Although EML4-ALK (with multiple fusion breakpoints in EML4) remains the major fusion variant in ALK+ NSCLC (accounting for approximately 95% of ALK fusion variants5), multiple case reports have reported novel ALK fusion partners in ALK+ NSCLC. In this article, we have compiled a list of the ALK fusion partners including intergenic rearrangements identified in the literature for easy reference.

Methods and Results

We searched PubMed publications, conference/congress abstracts, and presentations extensively to identify novel ALK fusion partners (including noncoding RNAs). We included only those fusion partners that retained the 3’ALK kinase domain. Reciprocal/nonreciprocal ALK translocations involving 5-ALK gene rearrangements (most frequently ALK exons 1-19 fused to a 3’-truncated gene [ALK-XXX]) were not listed although these nonfunctional 5’-ALK fusion variants are usually listed as ALK fusion variants in the literature. Overall, a total of 90 distinct ALK fusion partners (including noncoding RNAs) have been identified in the literature (by the end of January 2020) (Table 1). Many of these novel ALK fusion variants have been reported to respond to ALK TKIs or shown to be ALK IHC positive. Twenty-five intergenic rearrangements to exon 20 of ALK have also been identified and listed separately in Table 2. Three of these intergenic ALK rearrangements have been shown to respond to crizotinib, but the significance of these intergenic rearrangements remains to be determined, including whether functional fusion RNAs are translated from these intergenic rearrangements.

Table 1.

Catalog of Fusion Partners in ALK+ NSCLC

No. Fusion Partner Year
Published in Print/Presented		 Chromosomal Location Fusion Breakpoint Response to ALK TKI at the Time of Publication Tumor Source Method of Detection Variant Frequency in Tumor FISH/ IHC Referencesa
1 EML4 2007 2p21 (E13, A21)
(E20, A21)		 Not treated with ALK TKI Tumor PCR/Sanger sequencing NR ND/ND Soda, 20071
2007 2p21 (E13, A20) Not treated with ALK TKI Cell line/Tumor 5’RACE PCR
DNA sequencing		 NR ND/ND Rikova, ,20072
2 TFG 2007 3q12.2 (T3, A20) Not treated with ALK TKI Tumor 5’RACE PCR
DNA sequencing		 NR ND/ND Rikova, 20072
2007 3q12.2 NR Not treated with ALK TKI Tumor PCR/Sanger sequencing NR ND/ND Soda, 20071
3 KIF5B 2009 10p11.22 (K24, A20) Not treated with ALK TKI Tumor RT-PCR NR +/+ Takeuchi, 20096
2011 10p11.22 (K15, A20) Not treated with ALK TKI Tumor RT-PCR NR +/+ Won, 20117
2012 10p11.22 (K17, A20) Not treated with ALK TKI Tumor RT-PCR NR +/+ Takeuchi, 20128
4 KLC1 2012 14q32.33 (K9, A 20) Not treated with ALK TKI Tumor RT-PCR NR +/ND Togashi, 20129
5 STRN 2013 2p22.2 (S3, A20) NR Tumor RT-PCR NR +/+ Majewski, 201310
2017 2p22.2 (S3, A20) PR to crizotinib Plasma DNA NGS 1% ND/ND Yang, 201711
2017 2p22.2 (S3, A20) PR to alectinib Tumor RNA sequencing NR +/+ Nakanishi, 201712
STRNb 2019 2p22.2 (S3, A20) Not treated with ALK TKI Tumor DNA NGS NR NR/NR Xu, 201913
6 HIP1 2014 7q11.23 (H2, A20) Not treated with ALK TKI Tumor RNA sequencing NR ND/ND Fang, 201414
2014 7q11.23 (H21, A 20) PR to crizotinib Tumor RT-PCR NR +/+ Hong, 201415
2014 7q11.23 (H30, A20) PR to crizotinib and alectinib Tumor DNA NGS NR +/ND Ou, 201416
7 TPR 2014 1q31.1 (T15, A20) Not treated with ALK TKI Tumor PCR NR +/+ Choi, 201417
8 BIRC6 2015 2p22.3 NR PR to crizotinib Tumor DNA NGS NR -/+ Shan 201518
9 DCTN1 2015 2p13.1 (D26, A20) NR Tumor DNA NGS NR +/ND Iyevleva, 201519
10 SQSTM1 2015 5q35.3 (S5, A20) NR Tumor DNA NGS NR +/ND Iyevleva, 201519
11 SOCS5 2015 2p21 NR NR Tumor NGS NR -/ND Drilon, 201520
12 SEC31A 2016 4q21.22 (S21, A20) Adjuvant setting, not treated with ALK TKI Tumor NGS NR +/+ Kim, 201621
13 CLTC 2016 17q23.1 (C31, A20) Unknown Tumor NGS NR NR/NR Ali, 201622
14 PRKAR1A 2016 17q24.2 (P5, A20) PR to crizotinib Tumor NGS NR +/+ Ali, 201622
15 PPM1B 2016 2p21 (P1, A20) PR to crizotinib Tumor NGS NR NR/NR Ali, 201622
16 EIF2AK3 2016 2p11.2 (E2, A20) PR to crizotinib Tumor NGS NR -/- Ali, 201622
17 CRIM1 2016 2p22.2 NR NR Tumor NGS NR NR/NR Tan, 201623
18 CEBPZ 2017 2p22.2 (C2, A20) Not treated with ALK TKI Tumor NGS 25.3% +/+ Li, 201724
CEBPZb 2019 2p22.2 NR Crizotinib, unknown results Tumor NGS NR NR/NR Xu, 201913
19 PICALM 2017 11q14.2 (P19, A20) Not treated with ALK TKI Tumor NGS 10.2% -/+ Li, 201724
20 CLIP1 2017 12q24.31 (C22, A20) PR to crizotinib Tumor Targeted RNA sequencing NR +/+ Vendrelll, 201725
21 BCL11A 2017 2p16.1 (B4, A20) PR to crizotinib Tumor DNA and RNA NGS NR ND/ND Tian, 201726
BCL11Ac 2019 2p16.1 (B2, A18) PR to crizotinib Tumor and plasma DNA NGS 54.2% (PPFE)
14.9% (plasma)		 ND/ND Qin 201927
22 GCC2 2017 2q12.3 (G12, A20) NR Tumor RT-PCR, NGS NR +/+ Noh, 201728
2017 2q12.3 (G19, A20) Adjuvant setting, not treated with ALK TKI Tumor Targeted RNA sequencing NR +/+ Vendrelll, 201725
2018 2q12.3 (G18, A20) PR to crizotinib and then ceritinib Tumor RT-PCR, sanger sequencing NR NR/NR Jiang, 201829
23 LMO7 2017 13q22.2 (L15, A20) NR Tumor RT-PCR, NGS NR +/+ Noh, 201728
24 PHACTR1 2017 6p24.1 (P7, A20) NR Tumor RT-PCR, NGS NR +/+ Noh, 201728
25 CMTR1 2018 6p21.2 (C2, A20) No with crizotinib, SD with pemetrexed Tumor NGS ∼7.5% -/- Du, 201830
26 VIT 2018 2p22.2 (V7, A20) PR to alectinib Tumor NGS NR +/+ Hu, 201831
27 DYSF 2018 2p13.2 NR Extracranial PR but intracranial progression to crizotinib Pleural effusion DNA NGS 23.7% ND/+ Yin 201832
28 ITGAV 2018 2q32.1 NR Extracranial PR but intracranial progression to crizotinib Pleural effusion DNA NGS 15.2% ND/+ Yin, 201832
29 PLEKHA7b 2018 11p15.2-p15.1 (P26, A19) PR to alectinib + osimertinib Plasma DNA NGS NR ND/ND Schrock, 201833
30 CUX1 2018 7q22.1 (C8, A20) PR to crizotinib Tumor NGS 11% NR/NR Zhang 201834
31 VKORC1L1 2018 7q11.21 (V1, A20) PR with crizotinib and alectinib Plasma NGS NR +/ND Zhu, 201835
32 FBXO36 2018 2q36.3 NR PR to crizotinib Tumor NGS NR ND/+ Xu, 201836
33 SPTBN1c 2018 2p16.2 NR NR Plasma NGS NR NR/NR Ramalingam, 201837
34 EML6d 2018 2p16.1 (E1, A20) PR to crizotinib Tumor NGS NR ND/+ Lin, 201838
35 FBXO11d 2018 2p16.3 (F1, A20) PR to crizotinib Tumor NGS NR ND/+ Lin, 201838
36 CLIP4 2018 2p23.2 (C7, A20) NR Tumor NGS NR ND/+ Zhao, 201839
37 CAMKMT 2019 2p21 (C3, A 20) Not treated with ALK TKI Tumor NGS NR +/+ Hu, 201940
38 NCOA1 2019 2p23.3 (N12, A20) PR to crizotinib, PFS > 18 months Tumor NGS NR ND/+ Cao, 201941
39 MYT1L 2019 2p25.3 (M14, A20) PR on crizotinib, PD on ceritinib and alectinib Tumor NGS NR -/ND Tsou, 201942
40 SRBD1 2019 2p21 (S20, A20) Not treated with ALK TKI Tumor NGS 2.6% ND/+ Hou, 201943
41 SRD5A2 2019 2p23.1 (S1, A20) NR Tumor NGS NR ND/+ Zhao, 201944
42 NYAP2 (KIAA 1486) 2019 2q36.3 (N3, A20) NR Tumor NGS NR ND/- Zhao, 201944
43 MPRIP 2019 17p11.2 (M21, A20) PR to crizotinib Tumor RNA sequencing NR +/+ Fan, 201945
44 ADAM17 2019 2p25.1 (A4, A20) PR to alectinib Plasma DNA NGS 3.68% NR/NR Supplee, 201946
45 ALK 2019 2p23.2-p23.1 (A6, A20) NR Plasma DNA NGS 26.63% NR/NR Supplee, 201946
46 LPIN1b 2019 2p25.1 NR Response to crizotinib + erlotinib Tumor NR NR NR/NR Supplee 201946
47 WDPCP 2019 2p15 (W17, A20) PR to crizotinib Tumor DNA NGS 52.6% +/+ He, 201947
48 CEP55 2019 10q23.33 (C3, A20) NR Tumor DNA NGS NR NR/NR Couëtoux du Tertr, 201948
49 ERC1e 2019 12p13.33 (E15, A20) NR Tumor DNA NGS NR NR/NR Couëtoux du Tertr, 201948
2019 12p13.33 NR NR Tumor/plasma DNA NGS NR NR/NR Zhou, 201949
50 SLC16A7e 2019 12q14.1 (S1, A 20) PR to crizotinib prolonged PFS Tumor DNA NGS NR NR/NR Couëtoux du Tertr, 201948
51 TNIP2 2019 4p16.3 (T5, A20) PR to crizotinib Tumor/plasma DNA NGS 0.1% (plasma)
3.3% (tumor)		 ND/+ Feng, 201950
52 ATAD2B 2019 2p24.1-p23.3 (A1, A20) Treated with crizotinib Tumor DNA NGS NR ND/+ Bai, 201951
53 SLMAP 2019 3p14.3 (S12, A20)
(S13, A20)		 Unknown, adjuvant treatment with crizotinib Tumor Anchored Multiplex RNA sequencing NR +/+ Paga, 201952
54 FBN1 2019 15q21.1 NR NR Tumor/plasma DNA NGS NR NR/NR Zhou, 201949
55 SWAP70 2019 11p15.4 NR NR Tumor/plasma DNA NGS NR NR/NR Zhou, 201949
56 TCF12 2019 15q21.3 NR NR Tumor/plasma DNA NGS NR NR/NR Zhou, 201949
57 TRIM66 2019 11p15.4 NR NR Tumor/plasma DNA NGS NR NR/NR Zhou, 201949
58 WNK3 2019 Xp11.22 NR NR Tumor/plasma DNA NGS NR NR/NR Zhou, 201949
59 AKAP8L 2019 19p13.12 NR ensartinib plasma DNA NGS NR NR/NR Horn,201953
60 SPECC1L 2019 22q11.23 (S9, A20) Not treated with ALK TKI Tumor DNA NGS NR NR/NR Pan, 201954
61 PRKCBf 2019 16p12.2-p12.1 (P2, A19) PR to crizotinib, disappearance of PRKCB-ALK fusion variant Tumor and plasma NGS 2.6% (tumor)
0.8% (plasma)		 NR/NR Luo, 201955
62 CDK15f 2019 2q33.1 (C10, A19) NR Tumor DNA NGS NR NR/NR Wen, 201956
63 LCLAT1 2019 2p23.1 NR NR Tumor DNA NGS NR NR/NR Wen, 201956
64 YAP1 2019 11q22.1 NR NR Tumor DNANGS NR NR/NR Wen, 201956
65 PLEKHM2 (SCLC) 2020 1p36.21 (P7, A20) SD to crizotinib and brigatinib Tumor NGS NR ND/+ Li, 202057
66 DCHS1 2020 11p15.4 NR PR or SD to ensartinib Tumor NGS NR NR/NR Yang, 202058
67 PPFIBP1 2020 12p11.23-p11.22 NR PR or SD to ensartinib Tumor NGS NR NR/NR Yang, 202058
68 ATP13A4 2020 3q29 (A9, A19) NR Tumor NGS NR NR/NR Tian, 202059
69 C12orf75 2020 12q23.3 (C1, A20) NR Tumor NGS NR NR/NR Tian, 202059
70 EPAS1 2020 2p21 (E1, A20) NR Tumor NGS NR NR/NR Tian, 202059
71 FAM179A (TOGARAM2) 2020 2p23.2 (F1, A20) NR Tumor NGS NR NR/NR Tian, 202059
2020 2p23.2 (F13, A20) NR Plasma NGS NR ND/NR Zhang, 202060
72 FUT8 2020 14q23.3 (F3, A20) NR Tumor NGS NR NR/NR Tian, 202059
73 LIMD1 2020 3p21.31 (L2, A20) NR Tumor NGS NR NR/NR Tian, 202059
74 LINC00327 2020 13q12.12 (L2, A20) NR Tumor NGS NR NR/NR Tian, 202059
75 LOC349160 2020 7q33 (L1, A20) SD to crizotinib Tumor NGS NR NR/NR Tian, 202059
76 LYPD1 2020 2q21.2 (L3, A20) NR Tumor NGS NR NR/NR Tian, 202059
77 RBM20 2020 10q25.2 (R1, A20) NR Tumor NGS NR NR/NR Tian, 202059
78 TACR1 2020 2p12 (T1, A20) PR to crizotinib Tumor NGS NR NR/NR Tian, 202059
79 TANC1 2020 2q24.2 (T3, A20) NR Tumor NGS NR NR/NR Tian, 202059
80 TTC27 2020 2p22.3 (T12, A20) NR Tumor NGS NR NR/NR Tian, 202059
81 TUBBB 2020 6p21.33 (T3, A20) NR Tumor NGS NR NR/NR Tian, 202059
82 SMPD4 2020 2q21.1 (S1, A20) NR Tumor NGS NR NR/NR Tian, 202059
83 SORCS1 2020 10q25.1 (S10, A20) NR Tumor NGS NR NR/NR Tian, 202059
84 LINC00211 2020 2p22.2 (L?, A20) PR with crizotinib and alectinib, SD with lorlatinib CSF NGS 33.2% NR/+ Li, 202061
85 SOS1 2020 2p22.1 (S2, A20) PR to crizotinib FFPE NGS NR ND/ND Chen, 202062
86 C9orf3 2020 9q22.32 (C12, A20) NR FFPE NGS 22.6% ND/+ Zhang, 202060
87 CYBRD1 2020 2q31.1 (C21, A20) NR FFPE NGS 12.5% ND/NR Zhang, 202060
88 MTA3g 2020 2p21 (M6, A 20) SD with crizotinib, no response to alectinib FFPE NGS 15.3% ND/NR Zhang, 202060
89 THADA 2020 2p21 (T25, A20) SD to crizotinib, PR to ceritinib Plasma NGS 0.3% ND/NR Zhang, 202060
90 TSPYL6f 2020 2p16.2 (T6, A20) PR to crizotinib, SD to alectinib FFPE NGS 8.5% ND/NR Zhang, 202060
91 WDR37 2020 10p15.3 (W6, A20) PR to crizotinib FFPE NGS 30.2% ND/NR Zhang, 202060
92 PLEKHH2 2020 2p21 (P6, A20) PR to alectinib FFPE Targeted
RNA seqencing		 NR +/+ M. Nagasaka, written communication, 2020
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+, positive; -, negative;

ALK, anaplastic lymphoma kinase; CSF, cerebrospinal fluid; FISH, fluorescence in situ hybridization; FFPE, formalin-fixed paraffin embedded; FNA, fine-needle aspiration; IHC, immunohistochemistry; ND, not done; NGS, next-generation sequencing; NR, not reported; PFS, progression-free survival; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor; ADAM17, ADAM metallopeptidase domain 17; AKAP8L, A-kinase anchoring protein 8 like; ATAD2B, ATPase family AAA domain containing 2B; ATP13A4, ATPase 13A4; BCL11A, BAF chromatin remodeling complex subunit; BIRC6, baculoviral IAP repeat containing 6; C12orf75, chromosome 12 open reading frame 75; CAMKMT, calmodulin-lysine N-methyltransferase; CDK15; cyclin dependent kinase 15; CEBPZ, CCAAT enhancer binding protein zeta; CLIP1, CAP-Gly domain containing linker protein family member 1; CLIP4, CAP-Gly domain containing linker protein family member 4; CMTR1, cap methyltransferase 1; CRIM1, cysteine rich transmembrane BMP regulator 1; CUX1, cut like homeobox 1; CYBRD1, cytochrome b reductase 1; DCHS1, dachsous cadherin-related 1; DCTN1, dynactin subunit 1; DYSF, dysferlin; EIF2AK3, eukaryotic translation initiation factor 2 alpha kinase 3; EML4, echinoderm microtubule-associated protein-like 4; EML6, EMAP like 6; EPAS1, endothelial PAS domain protein 1; ERC1, ELKS/RAB6-interacting/CAST family member 1; FAM179A, family with sequence similarity 179 member A; FBN1, fibrillin 1; FBXO11, F-box protein 11; FBXO36, F-box protein 36; FUT8, fucosyltransferase 8; GCC2, GRIP and coiled-coil domain containing 2; HIP1, huntingtin interacting protein 1; ITGAV, integrin subunit alpha V; KLC1, kinesin light chain 1; KIF5B, kinesin family member 5B; LCLAT1, lysocardiolipin acyltransferase 1; LIMD1, LIM domains containing 1; LINC00211, long intergenic non-protein coding RNA 211; LINC00327, long intergenic non-protein coding RNA 327; LMO7, LIM domain 7; LOC349160, uncharacterized LOC349160; LPIN1, lipin 1; LYPD1, LY6/PLAUR domain containing 1; MPRIP, myosin phosphatase Rho interacting protein; MTA3, metastasis associated 1 family member 3; MYT1L, myelin transcription factor 1 like; NCOA1, nuclear receptor coactivator 1; NYAP2, neuronal tyrosine-phosphorylated phosphoinositide-3-kinase adaptor 2; PHACTR1, phosphatase and actin regulator 1; PICALM, phosphatidylinositol binding clathrin assembly protein; PLEKHA7, pleckstrin homology domain containing A7; PLEKHH2, pleckstrin homology, MyTH4 and FERM domain containing H2; PLEKHM2, pleckstrin homology and RUN domain containing M2; PPFIBP1, Liprin-beta-1/PPF1A. binding protein 1; PPM1B, protein phosphatase, Mg2+/Mn2+ dependent 1B; PRKAR1A, protein kinase cAMP-dependent type I regulatory subunit alpha; PRKCB, protein kinase C beta; RBM20, RNA binding motif protein 20; SEC31A, SEC31 homolog A, COPII coat complex component; SLC16A7, solute carrier family 16 member 7; SLMAP, sarcolemma associated protein; SMPD4, sphingomyelin phosphodiesterase 4; SOCS5, suppressor of cytokine signaling 5; SORCS1, sortilin related VPS10 domain containing receptor 1; SOS1, Son of sevenless Ras/Rac guanine nucleotide exchange factor 1; SPECC1L, sperm antigen with calponin homology and coiled-coil domains 1 like; SRBD1, S1 RNA binding domain 1; SRD5A2, steroid 5 alpha-reductase 2; SPTBN1, spectrin beta, non-erythrocytic 1; SQSTM1, sequestosome 1; STRN, Striatin; SWAP70, switching B cell complex subunit SWAP70; TACR1, tachykinin receptor 1; TANC1, tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 1; TCF12, transcription factor 12; TFG, trafficking from ER to golgi regulator; THADA, THADA (thyroid adenoma associated) armadillo repeat containing; TNIP2, TNFAIP3 interacting protein 2; TOGARAM2, TOG array regulator of axonemal microtubules 2; TPR, translocated promoter region, nuclear basket protein; TRIM66, tripartite motif containing 66; TSPYL6, TSPY like 6; TTC27, tetratricopeptide repeat domain 27; TUBB, tubulin beta class I; VIT, vitrin; VKORC1L1, vitamin K epoxide reductase complex subunit 1 like 1; WDR37, WD repeat domain 37; WDPCP, WD repeat containing planar cell polarity effector; WNK3, WNK lysine deficient protein kinase 3; YAP1, Yes1 associated transcriptional regulator.

hThe earlier detected ALK fusion partners were not treated with crizotinib at the time of publication; but all of them have been shown to respond to ALK TKIs. The column entry is for the later discovery of ALK fusion partners.

a

The first report(s) are cited except when response information from ALK TKIs are from later reports on some of the rare fusion partners, or if the fusion is identified as a resistance mechanism to EGFR TKI.

b

ALK fusions identified as resistance to EGFR TKIs.

c

Dual fusion with EML4-ALK (E18, A20).

d

Dual fusions (EML6 and FBXO11) together.

e

Dual fusion (ERC1 and SLC16A7) together.

f

Dual fusion with EML4-ALK (E6, A20)

g

Dual fusion with EML4-ALK (E7; A18)

Table 2.

List of Chromosomal Locations of Intergenic Translocations With Potential Fusion Partners

No. Year
Published in Print/Presented		 Chromosomal Location Potential Fusion Partner
Gene		 Response to ALK TKI at the Time of Publication Tumor Source Method of Detection Variant Frequency in Tumor FISH/IHC References
1 2019 12q23.3 RIC8B NR Tumor NGS NR ND/NR Zhao, 201944
2 2019 2p21 LOC388942 (LINC01913) NR Tumor NGS NR ND/NR Zhao, 201944
2020 2p21 LOC388942 (LINC01913) NR Tumor NGS NR NR/NR Tian, 202059
3 2019 2q22.1-q22.2 LRP1B NR Tumor NGS NR ND/NR Zhao, 201944
4 2019 2p16.2 MIR4431 NR Tumor NGS NR ND/NR Zhao, 201944
5 2019 2p23.3 CENPA/DPYSL5 PR to crizotinib Tumor NGS NR +/+ Fei, 201963
6 2020 18q12.1 CDH2 NR Tumor NGS NR NR/NR Tian, 202059
7 2020 18q12.2 CELF4 NR Tumor NGS NR NR/NR Tian, 202059
8 2020 2p23.3 CENPA PR to crizotinib Tumor NGS NR NR/NR Tian, 202059
9 2020 15q13.3 CHRNA7 PR to crizotinib Tumor NGS NR NR/NR Tian, 202059
10 2020 2q14.3 CNTNAP5 NR Tumor NGS NR NR/NR Tian, 202059
11 2020 2p21 COX7A2L NR Tumor NGS NR NR/NR Tian, 202059
12 2020 2p13.2 DYSF NR Tumor NGS NR NR/NR Tian, 202059
13 2020 2p16.3 FSHR NR Tumor NGS NR NR/NR Tian, 202059
14 2020 13q12.11 GJB6 NR Tumor NGS NR NR/NR Tian, 202059
15 2020 3q22.3 LINC01210 NR Tumor NGs NR NR/NR Tian, 202059
16 2020 2p22.3 MEMO1 NR Tumor NGS NR NR/NR Tian, 202059
17 2020 2p22.3 MIR548AD NR Tumor NGS NR NR/NR Tian, 202059
18 2020 4q31.1 MGST2 NR Tumor NGs NR NR/NR Tian, 202059
19 2020 2q11.2 PDCL3 NR Tumor NGS NR NR/NR Tian, 202059
20 2020 2p22.2 QPCT NR Tumor NGS NR NR/NR Tian, 202059
21 2020 2p23.3 RAB10 NR Tumor NGS NR NR/NR Tian, 202059
22 2020 2p22.1 SLC8A1 NR Tumor NGS NR NR/NR Tian, 202059
23 2020 2q32.3 STK17B NR Tumor NGS NR NR/NR Tian, 202059
24 2020 6q24.1-q24.2 VTA1 NR Tumor NGS NR NR/NR Tian, 202059
25 2020 2p22.2 CDC42EP3a No response to crizotinib and alectinib Plasma NGS 13.0% ND/+ Zhang, 202060
26 2020 19q13.42 PR11-433C9.2 (PRPF31) NR Tumor NGS 18.6% ND/NR Zhang, 202060
27 2020 3p22.1 RPSA NR Tumor NGS 7.9% ND/+ Zhang, 202060
28 2020 2p23.3 UBXN2A NR Tumor NGS 25.4% ND/NR Zhang, 202060
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ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ND, not done; NGS, next-generation sequencing; NR, not reported; PR, partial response; SD, stable disease; CENPA, centromere protein A; CDC42EP3, CDC42 effector protein 3; CDH2, cadherin 2; CELF4, CUGBP Elav-like family member 4; CNTNAP5, contactin associated protein family member 5; COX7A2L; cytochrome c oxidase subunit 7A2 like; DPYSL5, dihydropyrimidinase like 5; DYSF, dysferlin; FSHR, follicle stimulating hormone receptor; GJB6, gap junction protein beta 6; LINC01210, long intergenic non-protein coding RNA 1210; LINC01913, long intergenic non-protein coding RNA 1913; LRP1B, LDL receptor related protein 1B; MEMO1, mediator of cell motility 1; MIR4431, microRNA 4431; MIR548AD, microRNA 548ad; MGST2, microsomal glutathione S-transferase 2; PDCL3, phosducin like 3; PRPF31, pre-mRNA processing factor 31; QPCT, glutaminyl-peptide cyclotransferase; RAB10, RAB10, member RAS oncogene family; RIC8B, RIC8 guanine nucleotide exchange factor B; RPSA, ribosomal protein SA; SLC8A1, solute carrier family 8 member A1; STK17B, serine/threonine kinase 17b; UBXN2A, UBX domain protein 2A; VTA1, vesicle trafficking 1.

a

Together with EML4-ALK (E6, A20) and breakpoint is 3’UTR of CDC43EP3 to exon 20 of ALK. +, positive.

Discussion

With the increasing adoption of NGS for molecular profiling of NSCLC, especially in China, the pace at which new fusion partners are being identified and reported has rapidly increased since 2018. In particular, from 2018 onwards, approximately 65 of the 90 fusion partners reported in the literature (calculated at the time page numbers were assigned for this publication) were almost exclusively identified from China, indicating the widespread use of NGS there. Dual in-frame 3’-ALK fusion variants with different 5’ fusion partners are now being recognized; however, whether the relative contribution of each of the dual ALK fusion variant to oncogenesis depends on the allele frequency of each fusion variant remains to be elucidated. We identified at least 28 intergenic 3’-ALK rearrangements. Whether these translate to a functional (and truncated)? ALK RNA fusion transcript and whether these intergenic rearrangements are related to the isolated 3’-ALK fusion signals remain to be determined.

The concluding perspectives are as follows:

  • 1.

    ALK+ NSCLC is a heterogeneous disease with at least 90 distinct fusion partners identified in the literature by January 2020;

  • 2.

    It is likely that many more fusion partners and intergenic rearrangements will continue to be identified with the ever-increasing adoption of targeted RNA sequencing and whole transcriptome sequencing owing to the need to identify rare actionable fusions such as NTRK and NRG1 fusions;

  • 3.

    The role of individual 3’-ALK fusion variant in a dual 3’-ALK fusion variants will need to be elucidated; and

  • 4.

    The functional significance of intergenic rearrangements remains to be determined.

We recommend that clinicians from around the world to continue to report these novel fusions or intergenic rearrangements with information on the exon or fusion breakpoints, response to ALK TKIs, allele frequency, and if possible, whether the tumor is ALK fluorescence in situ hybridization and IHC positive.

Footnotes

Disclosure: Dr. Ou has stock ownership and was on the scientific advisory board of Turning Point Therapeutics, Inc. (until Feb 28, 2019). He has received speaker honorarium from Merck, Roche/Genentech, Astra Zeneca, Takeda/ARIAD, and Pfizer and has received advisory fees from Roche/Genentech, Astra Zeneca, Takeda/ARIAD, Pfizer, Foundation Medicine Inc., and Spectrum. Dr. Zhu has received honoraria from AstraZeneca, Biocept, Roche-Foundation Medicine, Roche/Genentech, and Takeda, and has stock ownership of Turning Point Therapeutics, Inc. Dr. Nagasaka has received honorarium from Astra Zeneca and Tempus.

References

  • 1.Soda M., Choi Y.L., Enomoto M. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–566. doi: 10.1038/nature05945. [DOI] [PubMed] [Google Scholar]
  • 2.Rikova K., Guo A., Zeng Q. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190–1203. doi: 10.1016/j.cell.2007.11.025. [DOI] [PubMed] [Google Scholar]
  • 3.Benayed R., Offin M., Mullaney K. High yield of RNA sequencing for targetable kinase fusions in lung adenocarcinomas with no mitogenic driver alteration detected by DNA sequencing and low tumor mutation burden. Clin Cancer Res. 2019;25:4712–4722. doi: 10.1158/1078-0432.CCR-19-0225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Jonna S., Feldman R.A., Swensen J. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res. 2019;25:4966–4972. doi: 10.1158/1078-0432.CCR-19-0160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Ross J.S., Ali S.M., Fasan O. ALK. Fusions in a Wide Variety of Tumor Types Respond to Anti-ALK Targeted Therapy. Oncologist. 2017;22:1444–1450. doi: 10.1634/theoncologist.2016-0488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Takeuchi K., Choi Y.L., Togashi Y. KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin Cancer Res. 2009;15:3143–3149. doi: 10.1158/1078-0432.CCR-08-3248. [DOI] [PubMed] [Google Scholar]
  • 7.Wong D.W., Leung E.L., Wong S.K. A novel KIF5B-ALK variant in nonsmall cell lung cancer. Cancer. 2011;117:2709–2718. doi: 10.1002/cncr.25843. [DOI] [PubMed] [Google Scholar]
  • 8.Takeuchi K., Soda M., Togashi Y. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18:378–381. doi: 10.1038/nm.2658. [DOI] [PubMed] [Google Scholar]
  • 9.Togashi Y., Soda M., Sakata S. KLC1-ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One. 2012;7 doi: 10.1371/journal.pone.0031323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Majewski I.J., Mittempergher L., Davidson N.M. Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol. 2013;230:270–276. doi: 10.1002/path.4209. [DOI] [PubMed] [Google Scholar]
  • 11.Yang Y., Qin S.K., Zhu J. A rare STRN-ALK fusion in lung adenocarcinoma identified using next-generation sequencing-based circulating tumor DNA profiling exhibits excellent response to crizotinib. Mayo Clin Proc Innov Qual Outcomes. 2017;1:111–116. doi: 10.1016/j.mayocpiqo.2017.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Nakanishi Y., Masuda S., Iida Y., Takahashi N., Hashimoto S. Case report of non-small cell lung cancer with STRN-ALK translocation: a nonresponder to alectinib. J Thorac Oncol. 2017;12:e202–e204. doi: 10.1016/j.jtho.2017.08.009. [DOI] [PubMed] [Google Scholar]
  • 13.Xu H., Shen J., Xiang J. Characterization of acquired receptor tyrosine-kinase fusions as mechanisms of resistance to EGFR tyrosine-kinase inhibitors. Cancer Manag Res. 2019;11:6343–6351. doi: 10.2147/CMAR.S197337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Fang D.D., Zhang B., Gu Q. HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. J Thorac Oncol. 2014;9:285–294. doi: 10.1097/JTO.0000000000000087. [DOI] [PubMed] [Google Scholar]
  • 15.Hong M., Kim R.N., Song J.Y. HIP1-ALK, a novel fusion protein identified in lung adenocarcinoma. J Thorac Oncol. 2014;9:419–422. doi: 10.1097/JTO.0000000000000061. [DOI] [PubMed] [Google Scholar]
  • 16.Ou S.H., Klempner S.J., Greenbowe J.R. Identification of a novel HIP1-ALK fusion variant in non-small-cell lung cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to alectinib. J Thorac Oncol. 2014;9:1821–1825. doi: 10.1097/JTO.0000000000000368. [DOI] [PubMed] [Google Scholar]
  • 17.Choi Y.L., Lira M.E., Hong M. A novel fusion of TPR and ALK in lung adenocarcinoma. J Thorac Oncol. 2014;9:563–566. doi: 10.1097/JTO.0000000000000093. [DOI] [PubMed] [Google Scholar]
  • 18.Shan L., Jiang P., Xu F. BIRC6-ALK, a novel fusion gene in ALK break-apart FISH-negative lung adenocarcinoma, responds to crizotinib. J Thorac Oncol. 2015;10:e37–e39. doi: 10.1097/JTO.0000000000000467. [DOI] [PubMed] [Google Scholar]
  • 19.Iyevleva A.G., Raskin G.A., Tiurin V.I. Novel ALK fusion partners in lung cancer. Cancer Lett. 2015;362:116–121. doi: 10.1016/j.canlet.2015.03.028. [DOI] [PubMed] [Google Scholar]
  • 20.Drilon A., Wang L., Arcila M.E. Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res. 2015;21:3631–3639. doi: 10.1158/1078-0432.CCR-14-2683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kim R.N., Choi Y.L., Lee M.S. SEC31A-ALK fusion gene in lung adenocarcinoma. Cancer Res Treat. 2016;48:398–402. doi: 10.4143/crt.2014.254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Ali S.M., Hensing T., Schrock A.B. Comprehensive genomic profiling identifies a subset of crizotinib-responsive ALK-rearranged non-small cell lung cancer not detected by fluorescence in situ hybridization. Oncologist. 2016;21:762–770. doi: 10.1634/theoncologist.2015-0497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Tan D.S.W., Kim D.W., Thomas M. Genetic landscape of ALK+ non-small cell lung cancer (NSCLC) patients (pts) and response to ceritinib in ASCEND-1. J Clin Oncol. 2016;34(suppl 15):9064. doi: 10.1016/j.lungcan.2021.11.007. [DOI] [PubMed] [Google Scholar]
  • 24.Li W., Zhang J., Guo L., Chuai S., Shan L., Ying J. Combinational analysis of FISH and immunohistochemistry reveals rare genomic events in ALK fusion patterns in NSCLC that responds to crizotinib treatment. J Thorac Oncol. 2017;12:94–101. doi: 10.1016/j.jtho.2016.08.145. [DOI] [PubMed] [Google Scholar]
  • 25.Vendrell J.A., Taviaux S., Béganton B. Detection of known and novel ALK fusion transcripts in lung cancer patients using next-generation sequencing approaches. Sci Rep. 2017;7:12510. doi: 10.1038/s41598-017-12679-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Tian Q., Deng W.J., Li Z.W. Identification of a novel crizotinib-sensitive BCL11A-ALK gene fusion in a nonsmall cell lung cancer patient. Eur Respir J. 2017;49 doi: 10.1183/13993003.02149-2016. [DOI] [PubMed] [Google Scholar]
  • 27.Qin B.D., Jiao X.D., Liu K., Wu Y., Zang Y.S. Identification of a novel EML4-ALK, BCL11A-ALK double-fusion variant in lung adenocarcinoma using next-generation sequencing and response to crizotinib. J Thorac Oncol. 2019;14:e115–e117. doi: 10.1016/j.jtho.2019.01.032. [DOI] [PubMed] [Google Scholar]
  • 28.Noh K.W., Lee M.S., Lee S.E. Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. J Pathol. 2017;243:307–319. doi: 10.1002/path.4950. [DOI] [PubMed] [Google Scholar]
  • 29.Jiang J., Wu X., Tong X. GCC2-ALK as a targetable fusion in lung adenocarcinoma and its enduring clinical responses to ALK inhibitors. Lung Cancer. 2018;115:5–11. doi: 10.1016/j.lungcan.2017.10.011. [DOI] [PubMed] [Google Scholar]
  • 30.Du X., Shao Y., Gao H. CMTR1-ALK: an ALK fusion in a patient with no response to ALK inhibitor crizotinib. Cancer Biol Ther. 2018;19:962–966. doi: 10.1080/15384047.2018.1480282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Hu S., Li Q., Peng W., Feng C., Zhang S., Li C. VIT-ALK, a novel alectinib-sensitive fusion gene in lung adenocarcinoma. J Thorac Oncol. 2018;13:e72–e74. doi: 10.1016/j.jtho.2017.11.134. [DOI] [PubMed] [Google Scholar]
  • 32.Yin J., Zhang Y., Zhang Y., F Peng F., Y Lu Y. Reporting on two novel fusions, DYSF-ALK and ITGAV-ALK, coexisting in one patient with adenocarcinoma of lung, sensitive to crizotinib. J Thorac Oncol. 2018;13:e43–e45. doi: 10.1016/j.jtho.2017.10.025. [DOI] [PubMed] [Google Scholar]
  • 33.Schrock A.B., Zhu V.W., Hsieh W.S. Receptor tyrosine kinase fusions and BRAF kinase fusions are rare but actionable resistance mechanisms to EGFR tyrosine kinase inhibitors. J Thorac Oncol. 2018;13:1312–1323. doi: 10.1016/j.jtho.2018.05.027. [DOI] [PubMed] [Google Scholar]
  • 34.Zhang M., Wang Q., Ding Y. CUX1-ALK, a novel ALK rearrangement that responds to crizotinib in non-small cell lung cancer. J Thorac Oncol. 2018;13:1792–1797. doi: 10.1016/j.jtho.2018.07.008. [DOI] [PubMed] [Google Scholar]
  • 35.Zhu V.W., Schrock A.B., Bosemani T., Benn B.S., Ali S.M., Ou S.I. Dramatic response to alectinib in a lung cancer patient with a novel VKORC1L1-ALK fusion and an acquired ALK T1151K mutation. Lung Cancer (Auckl) 2018;9:111–116. doi: 10.2147/LCTT.S186804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Xu C.W., Wang W.X., Chen Y.P. Simultaneous VENTANA IHC and RT-PCR testing of ALK status in Chinese non-small cell lung cancer patients and response to crizotinib. J Transl Med. 2018;16:93. doi: 10.1186/s12967-018-1468-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Ramalingam S.S., Cheng Y., Zhou C. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Ann Oncol, LBA50. 2018;29(suppl 8):viii740. [Google Scholar]
  • 38.Lin H., Ren G., Liang X. A novel EML6-ALK FBXO11-ALK double fusion variant in lung adenocarcinoma and response to crizotinib. J Thorac Oncol. 2018;13:e234–e236. doi: 10.1016/j.jtho.2018.07.011. [DOI] [PubMed] [Google Scholar]
  • 39.Zhao J., Li Q., Lin G. Distribution, differences in clinical characteristics and resistance mechanism of ALK variants in Chinese lung cancer patients. J Thorac Oncol. 2018;13:S584. [Google Scholar]
  • 40.Hu X., Cui Q., Wang M. A novel CAMKMT exon3-ALK exon20 fusion variant was identified in a primary pulmonary mucinous adenocarcinoma. J Thorac Oncol. 2019;14:e11–e12. doi: 10.1016/j.jtho.2018.09.020. [DOI] [PubMed] [Google Scholar]
  • 41.Cao Q., Liu Z., Huang Y., Qi C., Yin X. NCOA1-ALK: a novel ALK rearrangement in one lung adenocarcinoma patient responding to crizotinib treatment. OncoTargets Ther. 2019;12:1071–1074. doi: 10.2147/OTT.S192367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Tsou T.C., Gowen K., Ali S.M. Variable response to ALK inhibitors in NSCLC with a novel MYT1L-ALK fusion. J Thorac Oncol. 2019;14:e29–e30. doi: 10.1016/j.jtho.2018.10.169. [DOI] [PubMed] [Google Scholar]
  • 43.Hou X., Xu H., Chen L. SRBD1-ALK, a novel ALK fusion gene identified in an adenocarcinoma patient by next-generation sequencing. J Thorac Oncol. 2019;14:e72–e73. doi: 10.1016/j.jtho.2018.11.027. [DOI] [PubMed] [Google Scholar]
  • 44.Zhao R., Zhang J., Han Y. 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. doi: 10.1007/s40291-019-00389-y. [DOI] [PubMed] [Google Scholar]
  • 45.Fang W., Gan J., Hong S., Lu F., Zhang L. MPRIP-ALK, a novel ALK rearrangement that responds to ALK inhibition in NSCLC. J Thorac Oncol. 2019;14:e148–e151. doi: 10.1016/j.jtho.2019.02.030. [DOI] [PubMed] [Google Scholar]
  • 46.Supplee J.G., Milan M.S.D., Lim L.P. Sensitivity of next-generation sequencing assays detecting oncogenic fusions in plasma cell-free DNA. Lung Cancer. 2019;134:96–99. doi: 10.1016/j.lungcan.2019.06.004. [DOI] [PubMed] [Google Scholar]
  • 47.He Z., Wu X., Ma S. Next-generation sequencing identified a novel WDPCP-ALK fusion sensitive to crizotinib in lung adenocarcinoma. Clin Lung Cancer. 2019;20:e548–e551. doi: 10.1016/j.cllc.2019.06.001. [DOI] [PubMed] [Google Scholar]
  • 48.Couëtoux du Tertre M., Marques M., Tremblay L. Analysis of the genomic landscape in ALK+ NSCLC patients identifies novel aberrations associated with clinical outcomes. Mol Cancer Ther. 2019;18:1628–1636. doi: 10.1158/1535-7163.MCT-19-0105. [DOI] [PubMed] [Google Scholar]
  • 49.Zhou X., Shou J., Sheng J. Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Cancer Sci. 2019;110:3382–3390. doi: 10.1111/cas.14177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Feng T., Chen Z., Gu J., Wang Y., Zhang J., Min L. The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma. Lung Cancer. 2019;137:19–22. doi: 10.1016/j.lungcan.2019.08.032. [DOI] [PubMed] [Google Scholar]
  • 51.Bai H., Jia X., Jin X. ATAD2B-ALK, a novel fusion in lung adenocarcinoma identified using next-generation sequencing (NGS) J Thorac Oncol. 2019;14:S844. [Google Scholar]
  • 52.Pagan C., Barua S., Hsiao S.J. Targeting SLMAP-ALK-a novel gene fusion in lung adenocarcinoma. Cold Spring Harb Mol Case Stud. 2019;5 doi: 10.1101/mcs.a003939. a003939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Horn L., Whisenant J.G., Wakelee H. Monitoring therapeutic response and resistance: analysis of circulating tumor DNA in patients with ALK+ lung cancer. J Thorac Oncol. 2019;14:1901–1911. doi: 10.1016/j.jtho.2019.08.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Pan Y., Zhang Y., Ye T. Detection of novel NRG1, EGFR, and MET Fusions in lung adenocarcinomas in the Chinese population. J Thorac Oncol. 2019;14:2003–2008. doi: 10.1016/j.jtho.2019.07.022. [DOI] [PubMed] [Google Scholar]
  • 55.Luo J., Gu D., Lu H., Liu S., Kong J. Coexistence of a novel PRKCB-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to crizotinib. J Thorac Oncol. 2019;14:e266–e268. doi: 10.1016/j.jtho.2019.07.021. [DOI] [PubMed] [Google Scholar]
  • 56.Wen S., Dai L., Wang L. Genomic signature of driver genes identified by target next-generation sequencing in Chinese non-small cell lung cancer. Oncologist. 2019;24:e1070–e1081. doi: 10.1634/theoncologist.2018-0572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Li T., Zhang F., Wu Z. PLEKHM2-ALK: A novel fusion in small-cell lung cancer and durable response to ALK inhibitors. Lung Cancer. 2020;139:146–150. doi: 10.1016/j.lungcan.2019.11.002. [DOI] [PubMed] [Google Scholar]
  • 58.Yang Y., Zhou J., Zhou J. Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial. Lancet Respir Med. 2020;8:45–53. doi: 10.1016/S2213-2600(19)30252-8. [DOI] [PubMed] [Google Scholar]
  • 59.Tian P, Liu Y, Zeng H, et al: Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes [epub ahead of print] J Cancer Res Clin Oncol. https://doi.org/10.1007/s00432-019-03116-6, accessed January 21, 2020. [DOI] [PubMed]
  • 60.Zhang Y., Zeng L., Zhou C. Detection of non-reciprocal/reciprocal ALK translocation as poor predictive marker in first-line crizotinib-treated ALK-rearranged non-small cell lung cancer patients. J Thorac Oncol. 2020 doi: 10.1016/j.jtho.2020.02.007. [DOI] [PubMed] [Google Scholar]
  • 61.Li Z., Li P., Yan B. Sequential ALK inhibitor treatment benefits patient with leptomeningeal metastasis harboring non-EML4-ALK rearrangements detected from cerebrospinal fluid: A case report. Thorac Cancer. 2020;11:176–180. doi: 10.1111/1759-7714.13259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Chen H.F., Wang W.X., Xu C.W. A novel SOS1-ALK fusion variant in a metastatic lung adenocarcinoma patient with remarkable response to crizotinib. Lung Cancer. 2020 doi: 10.1016/j.lungcan.2020.02.012. in press. [DOI] [PubMed] [Google Scholar]
  • 63.Fei X., Zhu L., Zhou H., Qi C., Wang C. A novel intergenic region between CENPA and DPYSL5-ALK exon 20 fusion variant responding to crizotinib treatment in a patient with lung adenocarcinoma. J Thorac Oncol. 2019;14:e191–e193. doi: 10.1016/j.jtho.2019.04.012. [DOI] [PubMed] [Google Scholar]

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