Pathogenic gene fusions are key actionable biomarkers in precision oncology

NRG1 is a pathogenic fusion receiving increasing attention, as it is associated with multiple poor prognostic factors^.5,6 NRG1 fusions are genetic alterations that involve the NRG1 gene being abnormally fused with another gene. These fusions are heterogeneous and have many different gene partners and breakpoints. NRG1 fusions result in increased cell signaling and growth and can lead to uncontrolled growth and cancer.^7-11

NRG1 fusions have been identified across many tumor types and generally occur in the absence of other driver mutations. The overall frequency of NRG1 fusions varies across tumor types, with the highest being found in lung cancer (0.3%-1.7%) and pancreatic cancer (0.5%-1.8%), with other tumor types having <1%.^12,13

Importantly, there is a significant enrichment in NRG1 fusions in invasive mucinous lung adenocarcinoma (27%-31%) and in KRAS wild-type pancreatic cancer (up to 6%).^7,14

Methods like RT-PCR, FISH, and IHC may fall short of detecting pathogenic gene fusions and have limitations in screening NRG1 fusions. Detection of NRG1 fusions poses challenges, as DNA-based NGS alone can miss pathogenic gene fusions and lead to false-negative and false-positive results. Comprehensive testing with RNA-based NGS, including both DNA and RNA sequencing, is recommended to capture these fusions that DNA-based NGS might miss. The detection of NRG1 fusions is particularly difficult without RNA-based NGS due to the diversity of gene fusion partners, varying breakpoints, and large intronic regions.^15-21

To learn more about NRG1 fusions and RNA-based testing please visit

https://www.findthefusions.com.

Coming soon

Next week we will be inviting you to join our latest Lab Talk with Dr. Kurt Shalper from Yale School of Medicine. During this session Dr. Shalper will discuss pathogenic gene fusions as oncogenic drivers and actionable biomarkers in precision oncology, focusing on NRG1 fusions.

^References:

^{1. Gao Qet al. Cell Rep. 2018;23(1):227-238.e3. doi:10.1016/j.celrep.2018.03.050. 2. Latyshevaet al.Nucleic Acids Res. 2016;44(10):4487-4503. doi:10.1093/nar/gkw282. 3. Heyer EEet al. Nat Commun. 2019;10(1):1388. doi:10.1038/s41467-019-09374-9. 4. Liu SV. Future Oncol. 2022;18(26):2865-2870. doi:10.2217/fon-2022-0073. 5. Drilon Aet al. J Clin Oncol. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307. 6. Rosas D et al. Cancers (Basel). 2021;13(20):5038. doi:10.3390/cancers13205038. 7. Laskin J et al. Ann Oncol. 2020;31(12):1693-1703. doi:10.1016/j.annonc.2020.08.2335. 8. Zhang C et al. BiochimBiophys Acta Rev Cancer. 2022;1877(3):188707. doi:10.1016/j.bbcan.2022.188707. 9. Drilon A et al. J Clin Oncol. 2021;39(25):2791-2802. doi:10.1200/JCO.20.03307. 10. Schram AM et al. Cancer Discov. 2022;12(5):1233-1247. doi:10.1158/2159-8290.CD-21-1119. 11. Geuijen CAW et al. Cancer Cell. 2018;33(5):922-936. doi:10.1016/j.ccell.2018.04.003. 12. Liu SV. Plain language summary of NRG1 fusions in cancer: current knowledge and treatment with afatinib and other drugs. Future Oncol. 2022;18(26):2865-2870. doi:10.2217/fon-2022-0073. 13. Drilon A, Somwar R, Mangatt BP, et al. Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers. Cancer Discov. 2018;8(6):686-695. doi:10.1158/2159-8290.CD-17-1004. 14. Jones MR et al. Clin Cancer Res. 2019;25(15):4674-4681. doi:10.1158/1078-0432.CCR-19-0191. 15. Liu SV et al. Future Oncol. 2022;18(26):2865-2870. doi:10.2217/fon-2022-0073. 16. Drilon A et al. Cancer Discov. 2018;8(6):686-695. doi:10.1158/2159-8290.CD-17-1004. 17. Jones MR et al. Clin Cancer Res. 2019;25(15):4674-4681. doi:10.1158/1078-0432.CCR-19-0191. 18. Bruno R et al. Diagnostics (Basel). 2020;10(8):521. doi:10.3390/diagnostics10080521. 19. Su D et al. J Exp Clin Cancer Res. 2017;36(1):121. doi:10.1186/s13046-017-0591-4. 20. Benayed R et al. Clin Cancer Res. 2019;25(15):4712-4722. doi:10.1158/1078-0432.CCR-19-0225. 21. Heydt C et al. BMC Med Genomics. 2021;14(1):62. doi:10.1186/s12920-021-00909-y}