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NTRK Gene Fusions in Oncology

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 Mutations
Chromosome Structure Changes
Single nucleotide substitutions in gene mutations graphic1,3 Small insertions and deletions in gene mutations graphic1,3
Amplifications or deletions in chromosome structure graphic1,3 Rearrangements and fusions in chromosome structure graphic1,2

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
ETV6-NTRK3 gene fusion mechanism graphic

A subset of gene fusions involve NTRK1, NTRK2, and NTRK3.6

Test Your Knowledge

Select all that apply.
A gene fusion is formed:

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

Normal TRK signaling graphic Normal TRK signaling graphic
  • 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

Aberrant TRK signaling graphic
  • 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

Watch the video to explore the pathogenesis of NTRK gene fusion–driven tumors

Test Your Knowledge

Select all that apply.
Which of the following statements are TRUE:

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

Adult
Pediatric
NTRK gene fusion frequency in adult cancers graphic NTRK gene fusion frequency in adult cancers graphic
NTRK gene fusion frequency in pediatric cancers graphic NTRK gene fusion frequency in pediatric cancers graphic

Planning for
your practice

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

3 NTRK genes and their fusion partners graphic

Visualizing NTRK genes’ characteristics7

NTRK1, NTRK2, and NTRK3 gene characteristics graphic
NTRK1, NTRK2, and NTRK3 gene characteristics graphic
NTRK1, NTRK2, and NTRK3 gene characteristics graphic

Planning for
your practice

The optimal detection method for NTRK gene fusions would require no prior knowledge of fusion breakpoints and/or fusion partner, regardless of tumor type, and addresses the unique structural challenges associated with NTRK gene fusions.8

Watch Dr Michelle Shiller address the challenges of NTRK gene fusion detection

Test Your Knowledge

Select all that apply.
Which of these is not a feature of NTRK gene fusions?

ADC, adenocarcinoma; AML, acute myelogenous leukemia; CMN, congenital mesoblastic nephroma; GC, guanine-cytosine; HNSCC, head and neck squamous cell carcinoma; IFS, infantile fibrosarcoma; MASC, mammary analogue secretory carcinoma; NTRK, neurotrophic tyrosine receptor kinase; PTC, papillary thyroid carcinoma; SBC, secretory breast cancer; TRK, tropomyosin receptor kinase.

References: 1. Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1:e000023. 2. Kummar S, Lassen UN. Target Oncol. 2018;13(5):545-556. 3. Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34. 4. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer. 2013;13(11):772-787. 5. Abel H, Pfeifer J, Duncavage E. Translocation detection using next-generation sequencing. In: Kulkarni S, Pfeifer J, eds. Clinical Genomics. New York, NY: Elsevier/Academic Press; 2015:151-164. 6. Febbo P, Champagne M. Comprehensive NTRK fusion detection, agnostic of the fusion partner, for optimal identification of rare genomic events using TruSight™ Oncology 500 [webinar]. Presented at: Drug Discovery 2019. https://www.labroots.com/virtual-event/drug-discovery-2019; February 27, 2019. 7. Farago AF, Taylor MS, Doebele RC, et al. Clinicopathologic features of non–small-cell lung cancer harboring an NTRK gene fusion. JCO Precis Oncol. 2018. 8. Meyerson M, Gabriel S, Getz G. Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet. 2010;11(10):685-696.