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. 2020 Mar 30;1(2):100037. doi: 10.1016/j.jtocrr.2020.100037

Catalog of 5′ fusion partners in RET+ NSCLC Circa 2020

Sai-Hong Ignatius Ou 1,∗, Viola W Zhu 1
PMCID: PMC8474217  PMID: 34589933

Abstract

Since the discovery of RET fusion–positive (RET+) NSCLC around late 2011 to early 2012, clinical trials of multikinase inhibitors and highly potent and selective RET tyrosine kinase inhibitors have indicated that RET fusion is an actionable oncogenic driver in NSCLC. There seems to be a differential response to multikinase inhibitors depending on the fusion partner (KIF5B-RET versus non–KIF5B-RET); thus, knowledge of the fusion partners in RET+ NSCLC is important. To date, we identified 48 unique fusion partners in RET from published literature and congress proceedings. Two of the novel fusion partners (CCNYL2 and TRIM24) were identified in RET fusions that emerged as resistant to EGFR tyrosine kinase inhibitors. In addition, multiple intergenic rearrangements were identified.

Keywords: 5′ fusion partners, RET, NSCLC, Selpercatinib, Pralsetinib, Whole-transcriptome sequencing

Introduction

RET fusion–positive (RET+) NSCLC was discovered in early 2012,1, 2, 3, 4 5 years after the discovery of ALK and ROS1 fusion–positive NSCLC. There have been prospective studies investigating multikinase inhibitors (MKIs) such as vandetanib, cabozantinib, lenvatinib, sorafenib, and RXDX-105, which revealed modest clinical activity.5, 6, 7, 8, 9 More importantly, differential responses were observed on the basis of the specific fusion partner KIF5B verus non-KIF5B in RET+ NSCLC. The KIF5B-RET variant in NSCLC seems to be more resistant to MKIs than the other dominant CCDC6-RET fusion variant.6,9 Two highly potent and selective RET tyrosine kinase inhibitors (TKIs), selpercatinib (LIBRETTO-001, NCT03157128) and pralsetinib (ARROW, NCT03037385),10,11 are undergoing clinical trials for RET+ and RET-mutated tumors. In addition, RET fusion is one of the major receptor tyrosine kinase fusions identified as a resistance mechanism to EGFR TKIs.12 We undertook this review to catalog the fusion partners identified in literature up to April 2020 for easy reference.

Methods and Results

We searched PubMed publications and conference or congress abstracts and presentations extensively to identify novel RET fusion partners (including noncoding RNAs). We also communicated with authors who had presented posters to obtain lists of novel fusion partners. We included only fusion partners that retained the 3′ RET kinase domain. Overall, a total of 48 distinct RET fusion partners have been identified in literature as of April 2020 (Table 1).1, 2, 3, 4, 5,7,9,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 The RET gene is located on chromosomal 10q11.21. A total of 11 fusion partners are located on the long arm of chromosome 10 (10q), and three of the fusion partners are located around 10q11. Given the discovery of RET+ NSCLC occurred about 5 years after that of ALK+ and ROS1+ NSCLC, many of these novel RET fusion variants have not been treated with either MKIs or highly selective RET TKIs. Multiple intergenic rearrangements, mostly to exon 12 of RET, have also been identified and listed separately in Table 2.31,35 To date, none of these intergenic RET rearrangements have been reported to respond to RET TKIs; thus, the significance of these intergenic rearrangements remains to be determined, including whether functional fusion RNAs can be transcribed from these intergenic rearrangements.

Table 1.

Catalog of Fusion Partners in RET+ NSCLC

No. Fusion Partner Year Presented/Published in Print With Page Numbers Chromosomal Location Fusion Breakpoint Response to RET TKI at the Time of Publication Tumor Source Method of Detection Variant Frequency in Tumor FISH/IHC References
1 KIF5B 2012 10p11.22 (K15, R12)
(K16, R12)
(K23, R12)		 Not treated with RET TKI FFPE RNA sequencing NR NR/NR Ju et al.1
2012 10p11.22 (K15, R12)
(K16, R12)
(K23, R12)
(K24, R8)		 Not treated with RET TKI FFPE RT-PCR, Sanger sequencing NR NR/+ Kohno et al.2
2012 10p11.22 (K15, R12)
(K16, R12)
(K23, R12)
(K23, R12)
(K24, R11)		 Not treated with RET TKI FFPE RT-PCR, Sanger sequencing NR NR/NR Takeuchi et al.3
2012 10p11.22 (K15, R12) Not treated with RET TKI FFPE NGS NR NR/NR Lipson et al.4
2012 10p11.22 (K15, R12)
(K22, R12)		 Not treated with RET TKI FFPE RT-PCR, Sanger sequencing NR NR/NR Yokota et al.13
2 CCDC6 2012 10q21.2 (C1, R12) Not treated with RET TKI FFPE RT-PCR, Sanger sequencing NR NR/NR Takeuchi et al.3
10q21.2 (C1, R12) Not treated with RET TKI Cell line RT-PCR NR NR/NR Matsubara et al.14
3 NCOA4 2012 10q11.22 (N6, R12) Not treated with RET TKI FFPE RT-PCR NR +/+ Wang et al.15
4 TRIM33 2013 1p13.2 (T14, R12) PR to cabozantinib FFPE NGS NR +/NR Drilon et al.16
5 RUFY2 2014 10q21.3 (R9, R12) Not treated with RET TKI FFPE Targeted RNA sequencing NR +/NR Zheng et al.17
6 CUX1 2014 7q22.1 C10, R12) Not treated with RET TKI FFPE Anchored multiple PCR, NGS NR +/NR Lira et al.18
7 KIAA1468/(RELCH)a 2014 18q21.33 (K10, R12) Not treated with RET TKI FFPE RT-PCT NR NR/NR Nakaoku et al.19
KIAA1468/(RELCH)a 2019 18q21.33 NR Treated with selpercatinib FFPE or plasma NGS NR NR/NR Drilon et al.20
RELCHa 2020 18q21.33 (R10, R12) Not treated with RET TKI FFPE NGS NR +/NR Jiang et al.21
8 MPRIP 2016 17p11.2 (M19, R12) Not treated with RET TKI FFPE Targeted RNA sequencing NR NR/NR Fang et al.22
9 CLIP1 2016 12q24.31 NR PR to cabozantinib FFPE NGS NR NR/NR Drilon et al.5
10 ERC1 2016 12p13.33 NR SD to cabozantinib FFPE NGS NR NR/NR Drilon et al.5
11 KIAA1217 2016 10p12.2-p12.1 (K11, R10) Not treated with RET TKI FFPE NGS NR +/NR Lee et al.23
12 MYO5C 2016 15q21.2 (M25, R12) SD to vandetanib FFPE NGS NR +/NR Lee et al.7
13 EPHA5 2017 4q13.1-q13.2 NR Response to RET TKI FFPE NGS NR NR/NR Gautschi et al.24
14 PICALM 2017 11q14.2 NR NR FFPE NGS NR NR/NR Gautschi et al.24
15 FRMDA4 (KIAA1294) 2017 10p13 (F12, R12) Not treated with RET TKI FFPE NGS NR +/NR Velcheti et al.25
16 RASSF4 2017 10q11.21 (R3, R12) Not treated with RET TKI FFPE NGS NR NR/NR Zehir et al.26
17 KIF13A 2018 6p22.3 (K18, R12) Not treated with RET TKI FFPE NGS NR NR/NR Zhang et al.27
18 WAC 2018 10p12.1-p11.2 (W3, R12) Not treated with RET TKI FFPE NGS NR NR/NR Velcheti et al.28
19 TBC1D32 (C6orf170) 2019 6q22.31 (T9, R12) Not treated with RET TKI FFPE NGS NR NR/NR Peng et al.29
20 EML4 2019 2p21 NR PR to RXDX-105 FFPE NGS NR NR/NR Drilon et al.9
21 PARD3 2019 10p11.22-p11.21 NR PR to RXDX-105 FFPE NGS NR NR/NR Drilon et al.9
22 ARHGAP12 2019 10p11.22 NR Treated with selpercatinib FFPE or plasma NGS NR NR/NR Drilon et al.20
2019 10p11.22 NR NR FFPE NGS NR NR/NR Liu et al.30
23 CCDC88C 2019 14q32.11-q32.12 NR Treated with selpercatinib FFPE or plasma NGS NR NR/NR Drilon et al.20
24 DOCK1b 2019 10q26.2 NR Treated with selpercatinib FFPE or plasma NGS NR NR/NR Drilon et al.20
25 RBPMSb 2019 8p12 NR Treated with selpercatinib FFPE or plasma NGS NR NR/NR Drilon et al.20
26 PRKAR1A 2019 17q24.2 NR Treated with selpercatinib FFPE or plasma NGS NR NR/NR Drilon et al.20
27 ADD3 2019 10q25.1-q25.2 (A1, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
28 ANKS1B 2019 12q23.1 (A1, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
29 CCDC186 2019 10q25.3 (C10, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
30 CCNYL2c 2019 10q11.21 (C6, R16) SD to combination of cabozantinib and osimertinib FFPE or plasma NGS NR NR/NR Zhang et al.31
31 PCM1 2019 8p22 (P29, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
32 PRKG1 2019 10q11.23-21.1 (P7, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
33 PTPRK 2019 6q22.33 (P3, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
34 SIRT1 2019 10q21.3 (S8, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
35 SORBS1 2019 10q24.1 (S8, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
36 TSSK4 2019 14q1 (T1, R12) NR FFPE or plasma NGS NR NR/NR Zhang et al.31
37 TRIM24 2019 7q33-q34 NR Treated with selpercatinib FFPE or plasma NGS NR NR/NR Drilon et al.20
TRIM24d 2019 7q33-q34 NR NR Plasma NGS NR NR/NR Rich et al.32
38 CCDC3 2019 10p13 NR NR FFPE NGS NR NR/NR Liu et al.30
39 CTNNA3 2019 10q21.3 NR NR FFPE NGS NR NR/NR Liu et al.30
40 DYDC1 2019 10q23.1 NR NR FFPE NGS NR NR/NR Liu et al.30
41 EML6 2019 2p16.1 NR NR FFPE NGS NR NR/NR Liu et al.30
42 PRKCQ 2019 10p15.1 NR NR FFPE NGS NR NR/NR Liu et al.30
43 PRPF18 2019 10p13 NR NR FFPE NGS NR NR/NR Liu et al.30
44 LSM14A 2020 19q13.11 (L9, R20) NR FFPE NGS NR +/NR Lv et al.33
45 GPRC5Be 2020 16p12.3 NR NR FFPE or plasma NGS NR NR/NR Lu et al.34
46 GPR139e 2020 16p12.3 NR NR FFPE or plasma NGS NR NR/NR Lu et al.34
47 ANK3 2020 10q21.2 NR NR FFPE or plasma NGS NR NR/NR Lu et al.34
48 EPC1f 2020 10p11.22 NR NR FFPE or plasma NGS NR NR/NR Lu et al.34
Open in a new tab

FFPE: formalin-fixed paraffin-embedded; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NGS, next-generation sequencing; NR: not reported; PR: partial response; RT-PCR, reverse transcriptase polymerase chain reaction; SD: stable disease; TKI, tyrosine kinase inhibitor.

a

KIAA1468 is the same as RELCH.

b

DOCK1-RET and RBPMS-RET occurred in the same tumor.

c

CCNYL2-RET as resistance to osimertinib (EGFR L858R).

d

TRIM24-RET as resistance to EGFR del 19.

e

GPRC5B and GPR139 were detected as dual fusions in one case.

f

EPC1 was detected as dual fusions in one case with the other fusion partner being KIF5B.

Table 2.

List of Chromosomal Locations of Intergenic Translocations With Potential Fusion Partners

No. Year
Presented/Published in Print		 Chromosomal Location Potential Fusion Partner
Gene		 RET Exon Fusion Response to RET TKI at the Time of Publication Tumor Source Method of Detection Variant Frequency in Tumor FISH/IHC References
1 2019 10p14-p13 CDC123a R12 Treated with capmatinib, unknown response FFPE NGS NR NR/NR Xu et al.35
2 2019 10q11.21 ALOX5 R11 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
3 2019 10q21.2 ANK3 R11 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
4 2019 10q25.2 DUSP5 R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
5 2019 10p13 FAM188A (MINDY3) R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
6 2019 10p15.1 IL2RA R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
7 2019 10q23.31 LOC101926942 (LINC02653) R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
8 2019 10p12.1 LOC105376468 R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
9 2019 10q11.21 LOC105378269 R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
10 2019 5p12 MRPS30 R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
11 2019 10p11.22 NRP1 R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
12 2019 16q23.2 PRCAT47 (ARLNC1) R11 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
13 2019 10p13 PTER R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
14 2019 10q21.1 UBE2D1 R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
15 2019 19p12 ZNF43 R12 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
16 2019 10p11.23 ZNF438 R11 NR FFPE or plasma NGS NR NR/NR Zhang et al.31
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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.

a

RET fusion as potential resistance to osimertinib for EGFR (del 19, T790M, C797G/S)

Discussion

The number of RET fusion partners identified in RET+ NSCLC as of April 2020 is about 48, which is fewer than the number of ALK fusion partners identified.36 Again, we expect that more fusion partners in RET+ NSCLC will be identified with the continual use of next-generation sequencing (NGS), including whole-transcriptome sequencing as the diagnostic platform migrates to exhaustively identify all the actionable driver mutations in NSCLC, particularly RET fusions, given the impending approval of selpercatinib and pralsetinib. Furthermore, not all the fusion partners identified in other tumor types such as thyroid cancer have been identified in RET+ NSCLC.26,37 Currently, only the KIF5B fusion partner in KIF5B-RET has been reported to confer poor response to MKIs,6,9 because the kinesin domain of KIF5B interacts with the kinase domain of RET to create a signaling hub rendering resistance to RET inhibition alone.38 With this catalog of 5′ fusion partners in RET+ NSCLC, we hope to increase awareness of the various fusion partners in RET+ NSCLC and stimulate further translational research.

Concluding Perspectives

  • 1.

    RET+ NSCLC is a heterogeneous disease with at least 48 distinct fusion partners identified in the literature as of April 2020.

  • 2.

    With the anticipated approval of selpercatinib and pralsetinib for RET+ NSCLC, many more fusion partners and intergenic rearrangements will likely be identified with the ever-increasing adoption of targeted RNA sequencing and whole-transcriptome sequencing because of the need to identify rare actionable fusions such as NTRK and NRG1 fusions in general, and also RET fusions in particular.

  • 3.

    RET fusions are also common receptor tyrosine kinase fusions identified as acquired resistance to EGFR TKIs. Two novel fusion partners (CCNYL2 and TRIM24) were identified as resistance mechanisms to EGFR TKI in EGFR+ NSCLC.

  • 4.

    The functional significance of intergenic rearrangements remains to be determined. In one study, intergenic rearrangements accounted for 7.7% of the RET fusions identified. However, it is yet to be determined whether these intergenic rearrangements are transcribed into functional RET RNA fusions.

  • 5.

    We recommend that clinicians from all over the world continue to report these novel fusions and intergenic rearrangements with information on the following: (1) exon or fusion breakpoints; (2) response to RET TKIs; (3) allele frequency; and (4) whether the tumor is RET-positive on fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), if possible. Although RET TKIs are being developed after ALK and ROS1 TKIs, RET detection by IHC and FISH has not gone through health agency regulations given that NGS is the primary companion diagnostic platform used to detect RET fusions; thus, not much is known about the sensitivity and specificity as well as the positive and negative predictive values of these two testing modalities. We do realize that the uptake and utility of IHC and FISH for RET detection may be limited when NGS is likely the first approved companion diagnostic platform for RET fusions and increasing uptake to identify even rarer actionable driver alterations such as NRG fusions.

Footnotes

Disclosure: Dr. Ou has stock ownership and was on the scientific advisory board of Turning Point Therapeutics, Inc. (until February 28, 2019); has received speaker honoraria from Merck, Roche/Genentech, AstraZeneca, Takeda/ARIAD, and Pfizer; and has received advisory fees from Roche/Genentech, AstraZeneca, Daiiki Sankyo, 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.

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