Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database.
Adenocarcinoma
/ genetics
Adult
Aged
Aged, 80 and over
Antigens, Differentiation, B-Lymphocyte
/ genetics
Female
Histocompatibility Antigens Class II
/ genetics
Humans
Lung Neoplasms
/ genetics
Male
Middle Aged
Neuregulin-1
/ genetics
Oncogene Proteins, Fusion
/ genetics
Prostatic Neoplasms
/ genetics
Receptors, Cell Surface
/ genetics
Syndecan-4
/ genetics
Tenascin
/ genetics
Vesicle-Associated Membrane Protein 2
/ genetics
EGF-like domain
ERBB
ERBB3
HER
HER 3
MAPK
NRG1
PIK
carcinoma
data drilling
gene fusion
gene rearrangement
genetics
lung
mRNA sequencing
molecular
neuregulin
next-generation sequencing
receptor heterodimerization
receptor tyrosine kinase
Journal
Genes, chromosomes & cancer
ISSN: 1098-2264
Titre abrégé: Genes Chromosomes Cancer
Pays: United States
ID NLM: 9007329
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
02
02
2021
received:
07
08
2020
accepted:
10
02
2021
pubmed:
15
2
2021
medline:
1
2
2022
entrez:
14
2
2021
Statut:
ppublish
Résumé
The fusion genes containing neuregulin-1 (NRG1) are newly described potentially actionable oncogenic drivers. Initial clinical trials have shown a positive response to targeted treatment in some cases of NRG1 rearranged lung adenocarcinoma, cholangiocarcinoma, and pancreatic carcinoma. The cost-effective large scale identification of NRG1 rearranged tumors is an open question. We have tested a data-drilling approach by performing a retrospective assessment of a de-identified molecular profiling database of 3263 tumors submitted for fusion testing. Gene fusion detection was performed by RNA-based targeted next-generation sequencing using the Archer Fusion Plex kits for Illumina (ArcherDX Inc., Boulder, CO). Novel fusion transcripts were confirmed by a custom-designed RT-PCR. Also, the aberrant expression of CK20 was studied immunohistochemically. The frequency of NRG1 rearranged tumors was 0.2% (7/3263). The most common histologic type was lung adenocarcinoma (n = 5). Also, renal carcinoma (n = 1) and prostatic adenocarcinoma (n = 1) were found. Identified fusion partners were of a wide range (CD74, SDC4, TNC, VAMP2, UNC5D), with CD74, SDC4 being found twice. The UNC5D is a novel fusion partner identified in prostate adenocarcinoma. There was no co-occurrence with the other tested fusions nor KRAS, BRAF, and the other gene mutations specified in the applied gene panels. Immunohistochemically, the focal expression of CK20 was present in 2 lung adenocarcinomas. We believe it should be considered as an incidental finding. In conclusion, the overall frequency of tumors with NRG1 fusion was 0.2%. All tumors were carcinomas. We confirm (invasive mucinous) lung adenocarcinoma as being the most frequent tumor presenting NRG1 fusion. Herein novel putative pathogenic gene fusion UNC5D-NRG1 is described. The potential role of immunohistochemistry in tumor identification should be further addressed.
Substances chimiques
Antigens, Differentiation, B-Lymphocyte
0
Histocompatibility Antigens Class II
0
NRG1 protein, human
0
Neuregulin-1
0
Oncogene Proteins, Fusion
0
Receptors, Cell Surface
0
SDC4 protein, human
0
Syndecan-4
0
TNC protein, human
0
Tenascin
0
UNC5D protein, human
0
VAMP2 protein, human
0
Vesicle-Associated Membrane Protein 2
0
invariant chain
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
474-481Informations de copyright
© 2021 Wiley Periodicals LLC.
Références
Meyer D, Yamaai T, Garratt A, et al. Isoform-specific expression and function of neuregulin. Development. 1997;124:3575-3586.
Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003;284:14-30.
Pankonin MS, Sohi J, Kamholz J, Loeb JA. Differential distribution of neuregulin in the human brain and spinal fluid. Brain Res. 2009;1258:1-11.
Kwon OB, Paredes D, Gonzalez CM, et al. Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci USA. 2008;105:15587-15592.
Birchmeier C, Nave KA. Neuregulin-1, a key axonal signal that drives Schwann cell growth and differentiation. Glia. 2008;56:1491-1497.
Dixon M, Lumsden A. Distribution of neuregulin-1 (nrg1) and erbB4 transcripts in embryonic chick hindbrain. Mol Cell Neurosci. 1999;13:237-258.
Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008;9:437-452.
Fernandez-Cuesta L, Plenker D, Osada H, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov. 2014;4:415-422.
Tsai CJ, Nussinov R. Emerging allosteric mechanism of EGFR activation in physiological and pathological contexts. Biophys J. 2019;117:5-13.
Bao J, Wolpowitz D, Role LW, Talmage DA. Back signaling by the Nrg-1 intracellular domain. J Cell Biol. 2003;161:1133-1141.
Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol. 2009;21:177-184.
Hobbs SS, Coffing SL, Le AT, et al. Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation. Oncogene. 2002;21:8442-8452.
Jonna S, Feldman RA, Swensen J, et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res. 2019;25:4966-4972.
Adélaïde J, Huang H-E, Murati A, et al. A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/NRG1 gene. Genes Chromosomes Cancer. 2003;37:333-345. https://doi.org/10.1002/gcc.10218.
Drilon A, Somwar R, Mangatt BP, et al. Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers. Cancer Discov. 2018;8:686-695.
Jung Y, Yong S, Kim P, et al. VAMP2-NRG1 fusion gene is a novel oncogenic driver of non-small-cell lung adenocarcinoma. J Thorac Oncol. 2015;10:1107-1111.
Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310:644-648. https://doi.org/10.1126/science.1117679.
Tomlins SA, Laxman B, Dhanasekaran SM, et al. Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature. 2007;448:595-599. https://doi.org/10.1038/nature06024.
Alhamar M, Tudor VI, Smith SC, et al. Gene fusion characterisation of rare aggressive prostate cancer variants-adenosquamous carcinoma, pleomorphic giant-cell carcinoma, and sarcomatoid carcinoma: an analysis of 19 cases. Histopathology. 2020;77:890-899.
Zhang Z, Karthaus WR, Lee YS, et al. Tumor microenvironment-derived NRG1 promotes antiandrogen resistance in prostate cancer. Cancer Cell. 2020;38(2):279-296. https://doi.org/10.1016/j.ccell.2020.06.005.
Nakaoku T, Tsuta K, Ichikawa H, et al. Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res. 2014;20:3087-3093.
Heining C, Horak P, Uhrig S, et al. NRG1 fusions in KRAS wildtype pancreatic cancer. Cancer Discov. 2018;8:1087-1095.
Jones MR, Williamson LM, Topham JT, et al. NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wildtype pancreatic ductal adenocarcinoma. Clin Cancer Res. 2019;25:4674-4681.
Cadranel J, Liu SV, Duruisseaux M, et al. Therapeutic potential of Afatinib in NRG1 fusion-driven solid tumors: a case series. Oncologist. 2020;26:7-16. https://doi.org/10.1634/theoncologist.2020-0379.
Trombetta D, Graziano P, Scarpa A, et al. Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by phospho-ErbB3 expression. Oncotarget. 2018;9:9661-9671.
Shin DH, Lee D, Hong DW, et al. Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung. Oncotarget. 2016;7:69450-69465.
Fernandez-Cuesta L, Thomas RK. Molecular pathways: targeting NRG1 fusions in lung cancer. Clin Cancer Res. 2015;21:1989-1994.
Gaborit N, Lindzen M, Yarden Y. Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3. Hum Vaccin Immunother. 2016;12:576-592.
Mishra R, Patel H, Alanazi S, Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev. 2018;12:355.
Duruisseaux M, Liu SV, Han JY, et al. NRG1 fusion-positive lung cancers: clinicopathologic profile and treatment outcomes from a global multicenter registry. J Clin Oncol. 2019;37(15):9081-9081.
Laskin J, Liu SV, Tolba K, et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol. 2020;20:27-25. https://doi.org/10.1016/j.annonc.2020.08.2335.
Dhanasekaran SM, Balbin OA, Chen G, et al. Transcriptome metaanalysis of lung cancer reveals recurrent aberrations in NRG1 and hippo pathway genes. Nat Commun. 2014;5:5893.
McCoach CE, Le AT, Gowan K, et al. Resistance mechanisms to targeted therapies in ROS1(+) and ALK(+) non-small cell lung cancer. Clin Cancer Res. 2018;24:3334-3347.
Pan Y, Zhang Y, Ye T, et al. Detection of novel NRG1, EGFR, and MET fusions in lung adenocarcinomas in the Chinese population. J Thorac Oncol. 2019;14:2003-2008.