Several types of genomic alterations can drive cancer development
Genomic alterations can drive cancer development by activating oncogenes or disrupting tumor suppressors.1
Alterations may occur as:
- Gene mutations (such as in single nucleotide substitutions, and insertions or deletions)1
- Changes to the structure of chromosome (eg, in copy number amplification and chromosomal rearrangements/fusions)2
Gene fusions are a common class of genetic alterations4
A gene fusion is a hybrid gene formed from 2 normally separate genes, through a variety of mechanisms4:
- Chromosome rearrangement (translocations, inversions, insertions, or deletions)
- Transcription read-through
- mRNA splicing
A subset of gene fusions involve NTRK1, NTRK2, and NTRK3.6
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ETV6, ETS variant 6; NTRK, neurotrophic tyrosine receptor kinase; mRNA, messenger ribonucleic acid.
References: 1. Yates LR, Seoane J, Le Tourneau C, et al. The European Society for Medical Oncology (ESMO) Precision Medicine Glossary. Ann Oncol. 2018;29(1):30-35. 2. Kumar-Sinha C, Chinnaiyan AM. Nat Biotechnol. 2018;36(1):46-60. 3. Lister Hill National Center for Biomedical Communications. What kind of gene mutations are possible? Genetics Home Reference: Your Guide to Understanding Genetic Conditions. US National Library of Medicine, National Institutes of Health, US Dept of Health and Human Services. https://ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations. Accessed February 13, 2018. 4. Latysheva NS, Babu MM. Discovering and understanding oncogenic gene fusions through data intensive computational approaches. Nucleic Acids Res. 2016;44(10):4487-4503. 5. Euhus DM, Timmons CF, Tomlinson GE. ETV6-NTRK3–Trk-ing the primary event in human secretory breast cancer. Cancer Cell. 2002;2(5):347-348. 6. Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34.
Active NTRK gene fusions are driver oncogenes1
Under normal conditions, TRK receptors mediate neurotrophin signaling2
- The TRK receptor family comprises 3 transmembrane proteins referred to as TRKA, TRKB, and TRKC, encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively
- TRK receptors are typically expressed in human neuronal tissue and play an essential role in the physiology, development, and function of the nervous system through activation by neurotrophins
NTRK gene fusions lead to TRK fusion proteins that are oncogenic drivers1,2
- A subset of gene fusions involve NTRK1, NTRK2, and NTRK3 2
- Activating NTRK gene fusions couple the tyrosine kinase domain with a 5’ fusion partner resulting in a chimeric TRK protein lacking the ligand binding domain1,2
- This leads to constitutive activation of the TRK receptor kinase domain, which promotes tumor cell proliferation and survival2
Test Your Knowledge
Select all that apply.
BDNF, brain-derived neurotrophic factor; DNA, deoxyribonucleic acid; ERK, extracellular signal-regulated kinase; mRNA, messenger ribonucleic acid; NGF, nerve growth factor; NT, neurotrophin; NTRK, neurotrophic tyrosine receptor kinase; TRK, tropomyosin receptor kinase; Tyr, tyrosinase.
References: 1. Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. 2. Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1:e000023.
NTRK gene fusions are associated with many human tumor types1,2
NTRK gene fusions are associated with a diverse range of solid tumors and hematologic malignancies1-3 and are generally mutually exclusive of other driver genomic alterations.3
NTRK gene fusion frequency across adult and pediatric cancers2,5-11
Testing for NTRK gene fusions is essential to identify patients who harbor these genomic alterations12
GIST, gastrointestinal stromal tumors; NTRK, neurotrophic tyrosine receptor kinase.
References: 1. Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS. Targeting TRK family proteins in cancer. Pharmacol Ther. 2017;173:58-66. 2. Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. 3. Cocco E, Scaltriti M, Drilon A. Nat Rev Clin Oncol. 2018;15(12):731-747. 4. Cisowski J, Bergo MO. What makes oncogenes mutually exclusive? Small GTPases. 2017;8(3):187-192. 5. Kim J, Lee Y, Cho HJ, et al. NTRK1 fusion in glioblastoma multiforme. PLoS One. 2014;9(3):e91940. 6. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Comm. 2014;5:4846. 7. Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1:e000023. 8. Bourgeois JM, Knezevich SR, Mathers JA, Sorensen PHB. Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors. Am J Surg Pathol. 2000;24(7):937-946. 9. Rubin BP, Chen C-J, Morgan TW, et al. Congenital mesoblastic nephroma t(12; 15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am J Pathol. 1998;153(5):1451-1458. 10. Brzeziańska E, Karbownik M, Migdalska-Sek M, Patuszak-Lewandoska D, Wloch J, Lewińska A. Molecular analysis of the RET and NTRK1 gene rearrangements in papillary thyroid carcinoma in the Polish population. Mutat Res. 2006;599(1-2):26-35. 11. Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet. 2014;46(5):444-450. 12. Kummar S, Lassen UN. Target Oncol. 2018;13(5):545-556
NTRK gene fusion characteristics to consider for detection
NTRK gene fusions occur in numerous tumor types with multiple fusion partners.1,2 Several methods exist to detect genomic alterations; however, features unique to NTRK gene fusions must be considered when testing for NTRK gene fusions.2
- Gene fusions occur between all 3 NTRK genes (NTRK1, NTRK2, NTRK3) and fusion partners1,2
- ≥50 different fusion partners; novel partners continue to be reported1,2
- Occur across tumor types and have currently been identified in ≥20 cancers1,2
- Multiple and inconsistent genomic breakpoint locations3,4
- Large intronic regions2
- Low-complexity, GC-rich regions5,6
- TRK proteins are endogenously expressed in some tumor/tissue types3
Gene fusions occur between all 3 NTRK genes and EACH OF several different fusion partners3
Visualizing NTRK genes’ characteristics7