Development of metastatic poorly differentiated thyroid cancer from a sub-centimeter papillary thyroid carcinoma in a young patient with a germline MET mutation - association or random chance?
MET mutation
MET overexpression
Papillary thyroid cancer
Poorly differentatied thyroid carcinoma
Journal
Thyroid research
ISSN: 1756-6614
Titre abrégé: Thyroid Res
Pays: England
ID NLM: 101469037
Informations de publication
Date de publication:
14 Aug 2021
14 Aug 2021
Historique:
received:
30
03
2021
accepted:
21
07
2021
entrez:
14
8
2021
pubmed:
15
8
2021
medline:
15
8
2021
Statut:
epublish
Résumé
Thyroid cancer dedifferentiation is an unusual observation among young patients and is poorly understood, although a recent correlation to DICER1 gene mutations has been proposed. A 28-year old patient presented with a sub-centimeter cytology-verified primary papillary thyroid carcinoma (PTC) and a synchronous lateral lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous metastasis of poorly differentiated thyroid carcinoma (PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion. The question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these tumors.
Sections du résumé
BACKGROUND
BACKGROUND
Thyroid cancer dedifferentiation is an unusual observation among young patients and is poorly understood, although a recent correlation to DICER1 gene mutations has been proposed.
CASE PRESENTATION
METHODS
A 28-year old patient presented with a sub-centimeter cytology-verified primary papillary thyroid carcinoma (PTC) and a synchronous lateral lymph node metastasis. Following surgery, histopathology confirmed a 9 mm oxyphilic PTC and a synchronous metastasis of poorly differentiated thyroid carcinoma (PDTC). Extensive molecular examinations of both lesions revealed wildtype DICER1 sequences, but identified a somatic ETV6-NTRK3 gene fusion and a MET germline variant (c.1076G > A, p.Arg359Gln). MET is an established oncogene known to be overexpressed in thyroid cancer, and this specific alteration was not reported as a single nucleotide polymorphism (SNP), suggestive of a mutation. Both the primary PTC and the metastatic PDTC displayed strong MET immunoreactivity. A validation cohort of 50 PTCs from young patients were analyzed using quantitative real-time PCR, revealing significantly higher MET gene expression in tumors than normal thyroid controls, a finding which was particularly pronounced in BRAF V600E mutated cases. No additional tumors apart from the index case harbored the p.Arg359Gln MET mutation. Transfecting PTC cell lines MDA-T32 and MDA-T41 with a p.Arg359Gln MET plasmid construct revealed no obvious effects on cellular migratory or invasive properties, whereas overexpression of wildtype MET stimulated invasion.
CONCLUSIONS
CONCLUSIONS
The question of whether the observed MET mutation in any way influenced the dedifferentiation of a primary PTC into a PDTC metastasis remains to be established. Moreover, our data corroborate earlier studies, indicating that MET is aberrantly expressed in PTC and may influence the invasive behavior of these tumors.
Identifiants
pubmed: 34389035
doi: 10.1186/s13044-021-00110-4
pii: 10.1186/s13044-021-00110-4
pmc: PMC8364030
doi:
Types de publication
Journal Article
Langues
eng
Pagination
19Subventions
Organisme : Cancerfonden
ID : Junior Clinical Investigator Award
Organisme : Svenska Sällskapet för Medicinsk Forskning
ID : Stora Etableringsanslaget
Informations de copyright
© 2021. The Author(s).
Références
Nat Rev Endocrinol. 2018 Nov;14(11):670-683
pubmed: 30131586
Pathol Res Pract. 1999;195(6):427-33
pubmed: 10399184
Oncogene. 1992 Jan;7(1):3-7
pubmed: 1531516
Thyroid. 2001 Aug;11(8):783-7
pubmed: 11525273
Mod Pathol. 2020 Dec;33(12):2458-2472
pubmed: 32737449
Otolaryngol Head Neck Surg. 2021 Feb 9;:194599821991465
pubmed: 33560176
J Clin Endocrinol Metab. 2013 Sep;98(9):E1562-6
pubmed: 23833040
Cancer Res. 2002 Dec 1;62(23):7025-30
pubmed: 12460923
Thyroid. 2020 Dec;30(12):1771-1780
pubmed: 32495721
Gland Surg. 2019 Dec;8(6):589-590
pubmed: 32042662
J Cell Biochem. 2009 Aug 15;107(6):1222-36
pubmed: 19530226
J Clin Endocrinol Metab. 2014 Jun;99(6):E1130-6
pubmed: 24617711
J Biol Chem. 1991 Nov 25;266(33):22087-90
pubmed: 1718989
Cancers (Basel). 2020 Jul 31;12(8):
pubmed: 32752127
Cell. 2014 Oct 23;159(3):676-90
pubmed: 25417114
Thyroid. 2017 Feb;27(2):182-188
pubmed: 27849443
Nat Genet. 1997 May;16(1):68-73
pubmed: 9140397
Hum Mutat. 2018 Mar;39(3):371-377
pubmed: 29219214
Clin Endocrinol (Oxf). 2000 Nov;53(5):635-44
pubmed: 11106926
J Clin Invest. 2013 Nov;123(11):4935-44
pubmed: 24135138
Endocrinology. 2004 Sep;145(9):4355-65
pubmed: 15192042
Mod Pathol. 2020 Jul;33(7):1264-1274
pubmed: 31937902
J Clin Invest. 2018 Aug 31;128(9):4086-4097
pubmed: 29990309
Oncogene. 1998 Aug 13;17(6):733-9
pubmed: 9715275
Genes Chromosomes Cancer. 2008 Dec;47(12):1025-37
pubmed: 18709663
Clin Cancer Res. 1995 Feb;1(2):147-54
pubmed: 9815967
Medicine (Baltimore). 2021 Jan 15;100(2):e24237
pubmed: 33466206
Eur J Surg Oncol. 2020 May;46(5):754-762
pubmed: 31952928
Cancers (Basel). 2021 Feb 05;13(4):
pubmed: 33562809
Am J Surg Pathol. 2005 Apr;29(4):544-9
pubmed: 15767811
Endocr Relat Cancer. 2020 May;27(5):295-308
pubmed: 32163919