Gastrointestinal cancers

NTRK tumour epidemiology

Gastrointestinal cancers account for 26% of the global cancer incidence burden and 35% of all cancer-related deaths; in 2018, there were an estimated 4.8 million new cases and 3.4 million related deaths worldwide [1]. This section focuses on colorectal cancer (CRC), as it represents the majority of NTRK-related GI tumours.

CRC is the most frequent type of gastrointestinal cancers and the third most commonly diagnosed cancer in males and the second in females, according to the World Health Organization (WHO). In 2020, the International Agency for Research on Cancer estimated the worldwide incidence of CRC to be 1,931,590 cases with 935,173 deaths and a 5-year prevalence of 5,253,335 [1, 2].

Prevalence of NTRK fusion

Following the identification of TPM3-NTRK1 as an oncogenic driver in CRC in 1986 [3], it took almost 30 years until Ardini et al. 2014 characterised the TPM3-NTRK1 rearrangement at the molecular level [4]. Further cases of CRC harbouring NTRK1/2/3 gene fusions involving different partner genes have been subsequently reported. The prevalence of such fusions in CRC is around 0.3% (see table below).

Gastrointestinal tumour other than CRC where NTRK gene fusions have been reported include gastrointestinal stromal tumors (GIST) that are wild KIT/PDGFRA wild type (WT) [19]. In a case series of 821 patients with GIST, 31 were KIT/PDGFRA WT. In total, 16% of the WT GIST patients (5/31) had a TRK expression, and 16% (5/31) tested positive for NTRK1(3/31) or NTRK3(2/31) fusions. Among the five patients harbouring NTRK fusions, an ETV6-NTRK3 chimeric transcript was detected in one patient. Interestingly, in NTRK WT patients, the tumor location was on the stomach in 53.8% of cases, whereas in patients with NTRK fusion, 20% had the tumor in the stomach, 40% in the small bowel, and 40% in the rectum.

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

NTRK1/3 fusions are most frequent in CRC, whereas only one case of NTRK2 fusion has been reported to date. The most common partners reported for NTRK1 include LMNA, TPM3, and TPR, while ETV6 and EML4 seem to be the preferred partners for NTRK3 (see table above).

References

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4. Ardini E, Bosotti R, Borgia AL et al. The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition. Mol Oncol 2014;8(8):1495-1507.
5. 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.
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11. Cocco E, Benhamida J, Middha S et al. Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF/KRAS are enriched for targetable kinase fusions. Cancer Res. 2019;79(6):1047-1053.
12. Vaňková B, Vaněček T, Ptáková N et al. Targeted next generation sequencing of MLH1-deficient, MLH1 promoter hypermethylated, and BRAF/RAS-wild-type colorectal adenocarcinomas is effective in detecting tumors with actionable oncogenic gene fusions. Genes Chromosomes Cancer. 2020;59(10):562-568.
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17. Brenca M, Rossi S, Polano M et al. Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. J Pathol. 2016;238(4):543-549.
18. Shi E, Chmielecki J, Tang CM et al. FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. J Transl Med. 2016;14(1):339.
19. Lee JH, Shin SJ, Choe EA et al. Tropomyosin-Related Kinase Fusions in Gastrointestinal Stromal Tumors. Cancers (Basel). 2022; 27;14(11):2659.