Cargando…

Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)

BACKGROUND/AIMS: Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clini...

Descripción completa

Detalles Bibliográficos
Autores principales: Lee, Ji-young, Kim, Su Yeon, Jo, Kwan Hoon, Mo, Eun Yeong, Kim, Eun Sook, Kim, Hye Soo, Han, Je Ho, Moon, Sung-dae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Association of Internal Medicine 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8925960/
https://www.ncbi.nlm.nih.gov/pubmed/34905813
http://dx.doi.org/10.3904/kjim.2021.311
_version_ 1784670136004771840
author Lee, Ji-young
Kim, Su Yeon
Jo, Kwan Hoon
Mo, Eun Yeong
Kim, Eun Sook
Kim, Hye Soo
Han, Je Ho
Moon, Sung-dae
author_facet Lee, Ji-young
Kim, Su Yeon
Jo, Kwan Hoon
Mo, Eun Yeong
Kim, Eun Sook
Kim, Hye Soo
Han, Je Ho
Moon, Sung-dae
author_sort Lee, Ji-young
collection PubMed
description BACKGROUND/AIMS: Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences. METHODS: We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells. RESULTS: The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W. CONCLUSIONS: We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W.
format Online
Article
Text
id pubmed-8925960
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Korean Association of Internal Medicine
record_format MEDLINE/PubMed
spelling pubmed-89259602022-03-24 Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2) Lee, Ji-young Kim, Su Yeon Jo, Kwan Hoon Mo, Eun Yeong Kim, Eun Sook Kim, Hye Soo Han, Je Ho Moon, Sung-dae Korean J Intern Med Original Article BACKGROUND/AIMS: Germline mutations of the rearranged during transfection (RET) gene cause multiple endocrine neoplasia type 2 (MEN2). About 85% of RET mutations in MEN2 occur in codon Cys634. The RET D631Y mutation has recently been discovered, and we have studied its molecular expression and clinical consequences. METHODS: We analyzed the clinical characteristics of a total of 34 D631Y variant MEN2 individuals from seven families. We also constructed wild-type and mutant C630Y, D631Y, and C634R/W expression vectors and investigated their effects on signaling pathways and ability to correct the phenotypes of RET mutant cells. RESULTS: The median ages at diagnosis of pheochromocytoma and medullary thyroid carcinoma (MTC) were higher in patients with RET D631Y variant MEN2 than in those with the C634R/W variant (49:53.5 years vs. 33.5:27 years, respectively), and the penetration of the D631Y mutation with respect to MTC was lower than that of the C634R/W mutation (32.3% vs. 90%). The effects of the mutant vectors on phosphorylation of RET signaling molecules and focus formation were significantly different from those of wild type, but there were no significant differences between the mutants. D631Y scored significantly higher for chemotaxis and wound healing than C630Y, but lower than C634R and C634W. CONCLUSIONS: We suggest that the tumorigenic potential conferred by the D631Y mutation is lower than that conferred by the C634R/W mutation, but higher than that conferred by C630Y. Thus, the risk level of the RET D631Y variant appears to be higher than that of C630Y and lower than that of C634R/W. Korean Association of Internal Medicine 2022-03 2021-12-15 /pmc/articles/PMC8925960/ /pubmed/34905813 http://dx.doi.org/10.3904/kjim.2021.311 Text en Copyright © 2022 The Korean Association of Internal Medicine https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Lee, Ji-young
Kim, Su Yeon
Jo, Kwan Hoon
Mo, Eun Yeong
Kim, Eun Sook
Kim, Hye Soo
Han, Je Ho
Moon, Sung-dae
Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)
title Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)
title_full Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)
title_fullStr Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)
title_full_unstemmed Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)
title_short Clinical features and signaling effects of RET D631Y variant multiple endocrine neoplasia type 2 (MEN2)
title_sort clinical features and signaling effects of ret d631y variant multiple endocrine neoplasia type 2 (men2)
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8925960/
https://www.ncbi.nlm.nih.gov/pubmed/34905813
http://dx.doi.org/10.3904/kjim.2021.311
work_keys_str_mv AT leejiyoung clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2
AT kimsuyeon clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2
AT jokwanhoon clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2
AT moeunyeong clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2
AT kimeunsook clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2
AT kimhyesoo clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2
AT hanjeho clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2
AT moonsungdae clinicalfeaturesandsignalingeffectsofretd631yvariantmultipleendocrineneoplasiatype2men2