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. 2020 Apr 28;1(3):100048. doi: 10.1016/j.jtocrr.2020.100048

A Catalog of 5’ Fusion Partners in ROS1-Positive NSCLC Circa 2020

Sai-Hong Ignatius Ou a,∗, Misako Nagasaka b,c
PMCID: PMC8474457  PMID: 34589944

Abstract

ROS1 fusion–positive (ROS1+) NSCLC was discovered in 2007, the same year as the discovery of ALK-positive (ALK+) NSCLC but has trailed ALK+ NSCLC in terms of development. There seems to be a differential response to ROS1 inhibitors, which depend on fusion partners (CD74, SLC34A2, or SDC4); thus, knowledge of the fusion partners in ROS1+ NSCLC is important. To date (end of February 2020), we have identified 24 unique 5’ fusion partners of ROS1 in ROS1+ NSCLC from published literature and congress proceedings. Thus, we published this catalog for easy reference.

Keywords: ROS1 fusion partner, Next-generation sequencing, ROS1-positive NSCLC

Introduction

ROS1 fusion–positive (ROS1+) NSCLC was discovered in 2007,—the same year as ALK fusion–positive (ALK+) NSCLC.1 It constitutes about 2.9% of all adenocarcinomas of the lung.2 The development of ROS1 TKIs has followed the development of ALK TKIs; but to date, there are only two U.S. Food and Drug Administration–approved ROS1 TKIs (crizotinib and entrectinib).3,4 Neel et al.5 reported that different ROS1 fusion partners determine the subcellular localization of the ROS1 fusion variant and the subsequent oncogenic potency of that ROS1 fusion variant. In addition, Li et al.6 suggested that ROS1 fusion partners (CD74-ROS1 versus non–CD74-ROS1) have a differential response to crizotinib, and, more importantly, have a predilection for central nervous system metastasis. Thus, it is important to have a catalog of fusion partners of ROS1 in ROS1+ NSCLC.

Methods and Results

We extensively searched publications in PubMed, conference abstracts and presentations, and the cBioPortal for Cancer Genomics website to identify novel ROS1 fusion partners (including noncoding RNAs). We included only 5’ fusion partners that retained the 3’-ROS1 kinase domain. Overall, a total of 24 distinct ROS1 fusion partners were identified in the literature by the end of February 2020 (Table 1). We did not include one case report, in which the ROS1 fusion variant arose as a resistance mechanism to EGFR TKI, but the fusion partner to ROS1 was a 3’ fusion partner (ROS1-ADGRG6). In that ROS1 fusion variant, the ROS1-ADGRG6 fusion variant was generated by the fusion of exons 1 to 33 of ROS1, which did not contain the ROS1 kinase domain to exons 2 to 26 of ADGRG6. However, as the patient responded to crizotinib treatment, there was likely a potential presence of a 3’ ROS1 fusion variant.7 Another case reported FAM135B as a fusion partner in ROS1+ NSCLC.8 However, on verification of the data in the cBioPortal for Cancer Genomics,9 it was noted that the patient sample (P-0006921-T01-IM5) contained an SLC34A2-ROS1 and a ROS1-FAM135B variant. In addition, the fusion breakpoint of ROS1-FAM135B was not recorded in the cBioPortal for Cancer Genomics. Given the nomenclature listed on the said portal, we interpreted, with the limited information available, that FAM135B would be a 3’ fusion partner generated from a nonreciprocal translocation rather than a true 5’ ROS1 fusion partner. Only one intergenic rearrangement has been reported in ROS1+ NSCLC (Table 2).

Table 1.

Catalog of Fusion Partners in ROS1-Positive NSCLC

No. Fusion Partner Year
Published in Print/Presented		 Chromosomal Location Fusion Breakpoint Response to ROS1 TKI at the Time of Publication Tumor Source Method of Detection Variant Frequency in Tumor (%) FISH/IHC References
1 CD74 2007 5q33.1 (C6, R34) Not treated with ROS1 TKI FFPE 5’ RACE
RT-PCR		 NR +/NR Rikova et al.1
2 SLC34A2 2007 4p15.2 (S4, R34) Not treated with ROS1 TKI HCC78 cell line 5’ RACE
RT-PCR		 NR +/NR Rikova et al.1
3 EZR 2012 6q25.3 (E10, R34) Not treated with ROS1 TKI FFPE 5’ RACE
RT-PCR		 NR +/NR Takeuchi et al.16
4 LRIG3 2012 12q14.1 (L16, R35) Not treated with ROS1 TKI FFPE 5’ RACE
RT-PCR		 NR +/NR Takeuchi et al.16
5 SDC4 2012 20q13.12 (S2, R32)
(S4, R32)
(S4, R34)		 Not treated with ROS1 TKI FFPE 5’ RACE
RT-PCR		 NR +/NR Takeuchi et al.16
6 TPM3 2012 1q21.3 (T8, R35) Not treated with ROS1 TKI FFPE 5’ RACE
RT-PCR		 NR +/NR Takeuchi et al.16
7 GOPC (FIG) 2012 6q22.1 NR Not treated with ROS1 TKI FFPE RT-PCR NR +/+ Rimkunas et al.17
2012 6q22.1 (G7, R35) Not treated with ROS1 TKI FFPE RT-PCR, NR NR/NR Suehara et al.18
8 KDREL2 2012 7p22.1 NR Not treated with ROS1 TKI PPFE DNA NGS NR NR/NR Govindan et al.19
9 CCDC6 2012 10q21.2 (C6, R34) Not treated with ROS1 TKI FFPE DNA NGS NR NR/NR Seo et al.20
10 LIMA1a 2012 12q13.12 NR Response to crizotinib FFPE NR NR +/NR Shaw et al.21
11 MSNa 2012 Xq12 (M9, R34) NR FFPE Targeted RNA sequencing NR +/NR Zheng et al. 22
2012 Xq12 NR Response to crizotinib FFPE Targeted RNA sequencing NR +/NR Shaw et al.21
12 CLTC 2014 17q23.1 (C31, R35) Not treated with ROS1 TKI FFPE RNA sequencing NR NR/NR TCGA23
13 TMEM106B 2015 7p21.3 (T3, R35) Not treated with ROS1 TKI FFPE DNA NGS NR NR/NR Ou et al.24
14 TPD52L1 2016 6q22.31 (T3, R33) Not treated with ROS1 TKI FFPE DNA NGS NR NR/NR Zhu et al.25
15 SLC6A17 2017 1p13.3 NR NR FFPE NGS NR NR/NR Zehir26www.cbioportal.org9
16 CEP72 2018 5p15.33 (C11, R23) Not treated with ROS1 TKI FFPE DNA NGS NR NR/NR Zhu et al.27
17 ZCCHC8 2018 12q24.31 NR Not treated with ROS1 TKI FFPE NGS NR NR/NR Park et al.28
2018 12q24.31 (Z2, R36) Response to crizotinib FFPE NGS NR +/NR Hicks et al.29
2018 12q24.31 (Z2, R36) Response to crizotinibb FFPE NGS NR NR/NR Zhu et al.30
18 SLMAP 2018 3p14.3 (S?, R35) Not treated with ROS1 TKI FFPE NGS NR NR/NR Park et al.28
19 MYO5C 2018 15q21.2 (M?, R35) Not treated with ROS1 TKI FFPE NGS NR NR/NR Park et al.28
20 TFG 2018 3q12.2 NR Not treated with ROS1 TKI FFPE NGS NR NR/NR Park et al.28
21 WNK1 2019 12p13.33 (W25, R34) PR to crizotinib FFPE NGS 19.3 NR/NR Liu et al.31
22 MLL3 (KMT2C) 2019 7q36.1 NR NR Plasma NGS NR NR/NR Dagogo-Jack et al.32
23 CTD-2021J15.1 (LINC00973) 2019 3 NR NR Plasma NGS NR NR/NR Dagogo-Jack et al.32
24 RBPMS 2020 8p12 (R1, R32) Response to crizotinib FFPE NGS 23.7 NR/NR Zhang et al.33
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5’ RACE RT-PCR, 5’ rapid amplification of CDA ends reverse transcription polymerase chain reaction; CCDC6, coiled-coil domain containing 6; CD74, cluster of differentiation 74; CEP72, centrosomal protein 72; CLTC, clathrin heavy chain; DCBLD1, discoidin, CUB and LCCL domain containing 1; EZR, ezrin; FFPE, formalin-fixed paraffin embedded; FISH, fluorescence in situ hybridization; GOPC (FIG), golgi associated PDZ and coiled-coil motif containing; IHC, immunohistochemistry; KMT2C (MLL3), lysine methyltransferase 2C; LIMA1, LIM domain and actin binding 1; LINC00973 (CTD-2021J15.1), long intergenic nonprotein coding RNA 973; LRIG3, leucine rich repeats and immunoglobulin-like domains 3; MSN, moesin; MYO5C, myosin VC; NGS, next-generation sequencing; NR, not reported; TFG, trafficking from ER to golgi regulator, TMEM106B, transmembrane protein 106B; TPM3, tropomyosin 3; PR, partial response; TKI, tyrosine kinase inhibitor; WNK1, WNK lysine deficient protein kinase 1; ZCCHC8; zinc finger CCHC-type containing 8.

a

Both fusions were detected and treated in the crizotinib phase 2 trial. The MSN-ROS1 fusion identified in the 2 reports was likely the same identical fusion variant. One report described the technique of its identification while the other report reported its response to crizotinib in the expand crizotinib phase 1 trial.

b

With concurrent de novo MET amplification.

Table 2.

List of Chromosomal Location of Intergenic Translocations With Potential ROS1 Fusion Partners

No. Year
Published in Print/Presented		 Chromosomal Location Potential Fusion Partner Gene RET Exon Fusion Response to ALK TKI At the Time of Publication Tumor Source Method of Detection Variant Frequency in Tumor FISH/IHC References
1 2019 6q22.1 DCBLD1c R35 NR FFPE DNA NGS NR NR/NR Xu et al.34
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FFPE, formalin-fixed paraffin embedded; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NGS, next-generation sequencing; NR, not reported; TKI, tyrosine kinase inhibitor.

c

DCBLD1 intergenic rearrangement–ROS1 was identified as a potential resistance RTK fusion to osimertinib in an EGFR+ patient with NSCLC (Del 19, T790M) in addition to RP11-565P22.6-NTRK1 fusion.

Discussion

The number of ROS1 fusion partners identified in ROS1+ NSCLC as of February 2020 is approximately 24, which is lower than that reported for ALK+ and RET+ NSCLC.10,11 It is quite surprising, given the fact that ROS1+ NSCLC was discovered in 2007, whereas RET+ NSCLC was discovered only in 2012, although RET fusions have been identified in other solid tumors, especially in thyroid cancer. The ROS1 gene is located on chromosome 6q22.1 and only two fusion partners are located near ROS1 (GOPC, TPD52L1), and one fusion partner, ERZ, is located on 6q25.3. Unlike ALK+ and RET+ NSCLC, only one intergenic rearrangement has been reported in ROS1+ NSCLC (Table 2).

Another unique feature of ROS1+ NSCLC is the high incidence of venous thromboembolic events.12, 13, 14 Given the potential role of fusion partners in affecting different oncogenic potencies on the ROS1 fusion variant,5 the potential differential response to crizotinib, and the predilection for central nervous system metastasis,6 identifying ROS1 fusion partners is essential to further advance the science and management of ROS1+ NSCLC. Although five fusion partners (CD74, SLC34A2, SDC4, ERZ, TPM3) made up most of the ROS1+ patients with NSCLC who were enrolled in the entrectinib trials, 23% of the patients diagnosed with ROS1+ NSCLC had unknown fusion partners.4 Thus, it is important for future prospective studies of ROS1 TKIs to identify the fusion partners as much as possible, so that future translational studies can be performed from hypotheses generated from the subgroup analysis of these trials.

Conclusions

  • 1.

    ROS1+ NSCLC is a heterogeneous disease with at least 24 distinct fusion partners identified in the literature up until February 2020; but fewer fusion partners were identified compared with ALK+ and RET+ NSCLC.

  • 2.

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

  • 3.

    We recommend clinicians worldwide to continue to report these novel fusions/intergenic rearrangements, with information on exon breakpoints/fusions, response to ROS1 TKI and allele frequency, and, if possible, whether the tumor is ROS1-positive on fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).

  • 4.

    In this ROS1 fusion partner catalog, most of the ROS1+ NSCLC did not undergo any FISH or IHC testing. Currently, the companion diagnostic test for ROS1 rearrangement approved by the U.S. Food and Drug Administration is next-generation sequencing (Oncomine Dx Target test, PMA numberP160045).15 But given that FISH and IHC are still routinely used to detect ROS1 fusion, we continue to encourage clinicians when they report novel 5’ ROS1 fusion partners to describe the FISH or IHC results if they had been performed.

Footnotes

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

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