NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States

作者：Prasad Manju L^*; Vyas Monika; Horne Matthew J; Virk Renu K; Morotti Raffaella; Liu Zongzhi; Tallini Giovanni; Nikiforova Marina N; Christison Lagay Emily R; Udelsman Robert; Dinauer Catherine A; Nikiforov Yuri E

来源：Cancer, 2016, 122(7): 1097-1107.

DOI：10.1002/cncr.29887

• neurotrophic tyrosine kinase
• receptor type 3
• ets variant 6 (NTRK3
• ETV6) fusion oncogene
• papillary thyroid carcinoma
• pediatric cancer
• thyroid neoplasms

BACKGROUNDAn increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children.
METHODSThe histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing.
RESULTSSeven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAF(V600E)) (13 of 27 tumors; 48%), 11 measured <2 cm, and 6 had lymphatic invasion (46%), with vascular invasion in 3. Fusion oncogene tumors, compared with BRAF(V600E) PTCs, were associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P = .05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P < .001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P = .02); BRAF(V600E) PTCs were predominantly the classic variant (12 of 13 vs 1 of 13 tumors). Two tumors metastasized to the lung, and both had fusion oncogenes (NTRK1/TPR, n = 1; RET/PTC1, n = 1).
CONCLUSIONSFusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation. Cancer 2016;122:1097-1107. (c) 2016 American Cancer Society Pediatric papillary thyroid carcinomas with oncogene fusions (neurotrophic tyrosine kinase receptor types 1 and 3 [NTRK1/NTRK3], RET/PTC) are associated with extensive disease and aggressive pathology. An unusually high prevalence of NTRK1/NTRK3 oncogene fusion is observed in this pediatric population from the northeast United States.

• 出版日期2016-4-1