Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study

Jes Sloth Mathiesen; Jens Peter Kroustrup; Peter Vestergaard; Kirstine Stochholm Krag; Per Løgstrup Poulsen; Åse Krogh Rasmussen; Ulla Feldt-Rasmussen; Mette Gaustadnes; Torben Falck Ørntoft; Thomas V O Hansen; Finn Cilius Nielsen; Kim Brixen; Christian Godballe; Anja Lisbeth Frederiksen

doi:10.1089/thy.2016.0411

Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study

Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Kirstine Stochholm Krag, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Mette Gaustadnes, Torben Falck Ørntoft, Thomas V O Hansen, Finn Cilius Nielsen, Kim Brixen, Christian Godballe, Anja Lisbeth Frederiksen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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Abstract

Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016. Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

Original language	English
Journal	Thyroid : official journal of the American Thyroid Association
Volume	27
Issue	2
Pages (from-to)	215-223
Number of pages	9
ISSN	1050-7256
DOIs	https://doi.org/10.1089/thy.2016.0411
Publication status	Published - 1 Feb 2017

Keywords

epidemiology
genetics
medullary thyroid carcinoma
medullary thyroid carcinoma-genetics
molecular biology

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10.1089/thy.2016.0411

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Mathiesen, J. S., Kroustrup, J. P., Vestergaard, P., Krag, K. S., Poulsen, P. L., Rasmussen, Å. K., Feldt-Rasmussen, U., Gaustadnes, M., Ørntoft, T. F., Hansen, T. V. O., Nielsen, F. C., Brixen, K., Godballe, C., & Frederiksen, A. L. (2017). Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study. Thyroid : official journal of the American Thyroid Association, 27(2), 215-223. https://doi.org/10.1089/thy.2016.0411

@article{746321bb39a340239db6e03d162d9312,

title = "Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study",

abstract = "Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016. Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.",

keywords = "epidemiology, genetics, medullary thyroid carcinoma, medullary thyroid carcinoma-genetics, molecular biology",

author = "Mathiesen, {Jes Sloth} and Kroustrup, {Jens Peter} and Peter Vestergaard and Krag, {Kirstine Stochholm} and Poulsen, {Per L{\o}gstrup} and Rasmussen, {{\AA}se Krogh} and Ulla Feldt-Rasmussen and Mette Gaustadnes and {\O}rntoft, {Torben Falck} and Hansen, {Thomas V O} and Nielsen, {Finn Cilius} and Kim Brixen and Christian Godballe and Frederiksen, {Anja Lisbeth}",

year = "2017",

month = feb,

day = "1",

doi = "10.1089/thy.2016.0411",

language = "English",

volume = "27",

pages = "215--223",

journal = "Thyroid : official journal of the American Thyroid Association",

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Mathiesen, JS, Kroustrup, JP, Vestergaard, P, Krag, KS , Poulsen, PL, Rasmussen, ÅK, Feldt-Rasmussen, U, Gaustadnes, M , Ørntoft, TF , Hansen, TVO, Nielsen, FC, Brixen, K, Godballe, C & Frederiksen, AL 2017, 'Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study', Thyroid : official journal of the American Thyroid Association, vol. 27, no. 2, pp. 215-223. https://doi.org/10.1089/thy.2016.0411

Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study. / Mathiesen, Jes Sloth; Kroustrup, Jens Peter; Vestergaard, Peter et al.
In: Thyroid : official journal of the American Thyroid Association, Vol. 27, No. 2, 01.02.2017, p. 215-223.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study

AU - Mathiesen, Jes Sloth

AU - Kroustrup, Jens Peter

AU - Vestergaard, Peter

AU - Krag, Kirstine Stochholm

AU - Poulsen, Per Løgstrup

AU - Rasmussen, Åse Krogh

AU - Feldt-Rasmussen, Ulla

AU - Gaustadnes, Mette

AU - Ørntoft, Torben Falck

AU - Hansen, Thomas V O

AU - Nielsen, Finn Cilius

AU - Brixen, Kim

AU - Godballe, Christian

AU - Frederiksen, Anja Lisbeth

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016. Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

AB - Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016. Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

KW - epidemiology

KW - genetics

KW - medullary thyroid carcinoma

KW - medullary thyroid carcinoma-genetics

KW - molecular biology

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U2 - 10.1089/thy.2016.0411

DO - 10.1089/thy.2016.0411

M3 - Journal article

C2 - 27809725

SN - 1050-7256

VL - 27

SP - 215

EP - 223

JO - Thyroid : official journal of the American Thyroid Association

JF - Thyroid : official journal of the American Thyroid Association

IS - 2

ER -

Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study

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