Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia

Marianthi Georgitsi; Anniina Raitila; Auli Karhu; Rob B van der Luijt; Cora M Aalfs; Timo Sane; Outi Vierimaa; Markus J Mäkinen; Karoliina Tuppurainen; Ralph Paschke; Oliver Gimm; Christian A Koch; Sadi Gündogdu; Anneke Lucassen; Marc Tischkowitz; Louise Izatt; Simon Aylwin; Gul Bano; Shirley Hodgson; Ernesto De Menis; Virpi Launonen; Pia Vahteristo; Lauri A Aaltonen

doi:10.1210/jc.2006-2843

Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia

Marianthi Georgitsi, Anniina Raitila, Auli Karhu, Rob B van der Luijt, Cora M Aalfs, Timo Sane, Outi Vierimaa, Markus J Mäkinen, Karoliina Tuppurainen, Ralph Paschke, Oliver Gimm, Christian A Koch, Sadi Gündogdu, Anneke Lucassen, Marc Tischkowitz, Louise Izatt, Simon Aylwin, Gul Bano, Shirley Hodgson, Ernesto De MenisVirpi Launonen, Pia Vahteristo, Lauri A Aaltonen

Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.

Research output: Contribution to journal › Article › peer-review

225 Citations (Scopus)

Abstract

CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.

OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.

DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.

SETTING: The study was conducted at nonprofit academic research and medical centers.

PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.

MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.

RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.

CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

Original language	English
Pages (from-to)	3321-5
Number of pages	5
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	92
Issue number	8
DOIs	https://doi.org/10.1210/jc.2006-2843
Publication status	Published - Aug 2007

Keywords

Amino Acid Sequence
Computer Simulation
Cyclin-Dependent Kinase Inhibitor p27
DNA/genetics
DNA Mutational Analysis
Germ-Line Mutation
Humans
Immunohistochemistry
Intracellular Signaling Peptides and Proteins/genetics
Molecular Sequence Data
Multiple Endocrine Neoplasia Type 1/genetics
Reverse Transcriptase Polymerase Chain Reaction

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10.1210/jc.2006-2843

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Georgitsi, M., Raitila, A., Karhu, A., van der Luijt, R. B., Aalfs, C. M., Sane, T., Vierimaa, O., Mäkinen, M. J., Tuppurainen, K., Paschke, R., Gimm, O., Koch, C. A., Gündogdu, S., Lucassen, A., Tischkowitz, M., Izatt, L., Aylwin, S., Bano, G., Hodgson, S., ... Aaltonen, L. A. (2007). Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. Journal of Clinical Endocrinology and Metabolism, 92(8), 3321-5. https://doi.org/10.1210/jc.2006-2843

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title = "Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia",

abstract = "CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.SETTING: The study was conducted at nonprofit academic research and medical centers.PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.",

keywords = "Amino Acid Sequence, Computer Simulation, Cyclin-Dependent Kinase Inhibitor p27, DNA/genetics, DNA Mutational Analysis, Germ-Line Mutation, Humans, Immunohistochemistry, Intracellular Signaling Peptides and Proteins/genetics, Molecular Sequence Data, Multiple Endocrine Neoplasia Type 1/genetics, Reverse Transcriptase Polymerase Chain Reaction",

author = "Marianthi Georgitsi and Anniina Raitila and Auli Karhu and {van der Luijt}, {Rob B} and Aalfs, {Cora M} and Timo Sane and Outi Vierimaa and M{\"a}kinen, {Markus J} and Karoliina Tuppurainen and Ralph Paschke and Oliver Gimm and Koch, {Christian A} and Sadi G{\"u}ndogdu and Anneke Lucassen and Marc Tischkowitz and Louise Izatt and Simon Aylwin and Gul Bano and Shirley Hodgson and {De Menis}, Ernesto and Virpi Launonen and Pia Vahteristo and Aaltonen, {Lauri A}",

year = "2007",

month = aug,

doi = "10.1210/jc.2006-2843",

language = "English",

volume = "92",

pages = "3321--5",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "8",

}

Georgitsi, M, Raitila, A, Karhu, A, van der Luijt, RB, Aalfs, CM, Sane, T, Vierimaa, O, Mäkinen, MJ, Tuppurainen, K, Paschke, R, Gimm, O, Koch, CA, Gündogdu, S, Lucassen, A, Tischkowitz, M , Izatt, L , Aylwin, S, Bano, G, Hodgson, S, De Menis, E, Launonen, V, Vahteristo, P & Aaltonen, LA 2007, 'Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia', Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 8, pp. 3321-5. https://doi.org/10.1210/jc.2006-2843

TY - JOUR

T1 - Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia

AU - Georgitsi, Marianthi

AU - Raitila, Anniina

AU - Karhu, Auli

AU - van der Luijt, Rob B

AU - Aalfs, Cora M

AU - Sane, Timo

AU - Vierimaa, Outi

AU - Mäkinen, Markus J

AU - Tuppurainen, Karoliina

AU - Paschke, Ralph

AU - Gimm, Oliver

AU - Koch, Christian A

AU - Gündogdu, Sadi

AU - Lucassen, Anneke

AU - Tischkowitz, Marc

AU - Izatt, Louise

AU - Aylwin, Simon

AU - Bano, Gul

AU - Hodgson, Shirley

AU - De Menis, Ernesto

AU - Launonen, Virpi

AU - Vahteristo, Pia

AU - Aaltonen, Lauri A

PY - 2007/8

Y1 - 2007/8

N2 - CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.SETTING: The study was conducted at nonprofit academic research and medical centers.PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

AB - CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.SETTING: The study was conducted at nonprofit academic research and medical centers.PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

KW - Amino Acid Sequence

KW - Computer Simulation

KW - Cyclin-Dependent Kinase Inhibitor p27

KW - DNA/genetics

KW - DNA Mutational Analysis

KW - Germ-Line Mutation

KW - Humans

KW - Immunohistochemistry

KW - Intracellular Signaling Peptides and Proteins/genetics

KW - Molecular Sequence Data

KW - Multiple Endocrine Neoplasia Type 1/genetics

KW - Reverse Transcriptase Polymerase Chain Reaction

U2 - 10.1210/jc.2006-2843

DO - 10.1210/jc.2006-2843

M3 - Article

C2 - 17519308

SN - 0021-972X

VL - 92

SP - 3321

EP - 3325

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 8

ER -

Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia

Abstract

Keywords

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