Thyroid Cancer

NTRK tumour epidemiology

In 2020, the International Agency for Research on Cancer estimated the worldwide incidence of thyroid cancer to be 586,202 cases with 43,646 deaths and a 5-year prevalence of 1,984,927 [1]. Thyroid cancers account for approximately 4% of malignancies in children [2]. The most common type of adult thyroid cancer, papillary thyroid carcinoma (PTC), accounts for 90% of all thyroid cancer cases, whereas anaplastic thyroid cancer (ATC) accounts for only 1-2% of cases [3]. The majority (~93%) of thyroid carcinomas in children are Differentiated Thyroid Cancers - DTC (papillary and follicular), ~5% of cases are medullary (MTC), and ~2% are a mix or rare forms.

Prevalence of NTRK fusion

NTRK1 was identified as an oncogenic driver in PTC by Bongarzone et al. in 1989 [4]. Since then, NTRK3 gene fusions have also been reported in PTC and thyroid cancers in general (see table below). Overall, the reported frequency of NTRK rearrangements in thyroid cancer has been shown to range from <5% to approximately 25%, with the highest prevalence noted in radiation-induced thyroid cancers [5], as well as in paediatric patients (see table below).

A study in a middle eastern patient cohort (N=315) reported that NTRK fusions were found to be significantly associated with younger age patients (p = 0.0117), lymph node metastasis (p = 0.0428) and BRAF wild-type tumors (p < 0.0001). Furthermore, NTRK gene fusions were significantly enriched in paediatric PTCs, compared to adult PTCs (19.2% vs 4.8%; p= 0.0143) [6].

Which NTRK fusion is more frequent: NTRK1/2/3 and partners?

NTRK3 fusions in PTC seem to occur more frequently than NTRK1 fusions, whereas no NTRK2 fusions have been reported to date. ETV6-NTRK3 is the most common rearrangement in PTC. While the prevalence of this rearrangement in adults with PTC is very low (<1%), it is the second most common rearrangement seen in radiation-associated PTC (see table above).

References

1. Ferlay J, Ervik M, Lam F et al. Global Cancer Observatory: Cancer Today. Lyon: International Agency for Research on Cancer; 2020 (https://gco.iarc.fr/today/fact-sheets-cancers)
2. Prasad M.L., Vyas M., Horne M.J et al. NTRK Fusion Oncogenes in Pediatric Papillary Thyroid Carcinoma in Northeast United States. Cancer. 2016; 122:1097–1107.
3. Rossi ED, Pantanowitz L, Hornick JL. A worldwide journey of thyroid cancer incidence centred on tumour histology. Lancet Diabetes Endocrinol. 2021;9(4):193-194.
4. Bongarzone I, Pierotti MA, Monzini N et al. High frequency of activation of tyrosine kinase oncogenes in human papillary thyroid carcinoma. Oncogene. 1989;4(12):1457-1462.
5. Ricarte-Filho JC, Li S, Garcia-Rendueles ME et al. Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Invest. 2013;123(11):4935-4944.
6. Kong Y, Bu R, Parvathareddy SK et al. NTRK fusion analysis reveals enrichment in Middle Eastern BRAF wild-type PTC. Eur J Endocrinol. 2021;184(4):503-511.
7. Leeman-Neill RJ, Kelly LM, Liu P et al. ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer. Cancer 2014;120(6):799-807.
8. Rosen EY, Goldman DA, Hechtman JF et al. TRK Fusions are enriched in cancers with uncommon histologies and the absence of canonical driver Mutations. Clin Cancer Res. 2020;26(7):1624-1632.
9. Solomon JP, Linkov I, Rosado A et al. NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol. 2020;33(1):38-46.
10. Okamura R, Boichard A, Kato S et al. Analysis of NTRK Alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics. JCO Precis Oncol. 2018;2018:PO.18.00183.
11. Gatalica Z, Xiu J, Swensen J, Vranic S. Molecular characterization of cancers with NTRK gene fusions. Mod Pathol. 2019;32(1):147-153.
12. Wajjwalku W, Nakamura S, Hasegawa Y et al. Low frequency of rearrangements of the ret and trk proto-oncogenes in Japanese thyroid papillary carcinomas. Jpn J Cancer Res. 1992;83(7):671-675.
13. Said S, Schlumberger M, Suarez HG. Oncogenes and anti-oncogenes in human epithelial thyroid tumors. J Endocrinol Invest. 1994;17(5):371-379.
14. Chu YH, Dias-Santagata D, Farahani AA et al. Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NTRC). Mod Pathol. 2020;33(11):2186-2197.