Cyclin-dependent kinase inhibitor 1B(CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds

Maria A. Tichomirowa, Misu Lee, Anne Barlier, Adrian F. Daly, Ilaria Marinoni, Marie Lise Jaffrain-Rea, Luciana A. Naves, Patrice Rodien, Vincent Rohmer, Fabio Rueda Faucz, Philippe Caron, Bruno Estour, Pierre Lecomte, Françoise Borson-Chazot, Alfred Penfornis, Maria Yaneva, Mirtha Guitelman, Emily Castermans, Catherine Verhaege, Jean Louis WeḿeauAntoine Tabarin, Carmen Fajardo Montanãna, Brigitte Delemer, Veronique Kerlan, Jean Louis Sadoul, Christine Cortet Rudelli, Françoise Archambeaud, Sabine Zacharieva, Marily Theodoropoulou, Thierry Brue, Alain Enjalbert, Vincent Bours, Natalia S. Pellegata, Albert Beckers

Research output: Contribution to journalArticle

Abstract

Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A > C (p.K96Q) and c.356T > C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27 I119T shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C > T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

Original languageEnglish
Pages (from-to)233-241
Number of pages9
JournalEndocrine-Related Cancer
Volume19
Issue number3
DOIs
Publication statusPublished - Jun 2012

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Cyclin-Dependent Kinase Inhibitor p27
Mutation
Genes
Pituitary Neoplasms
Carney Complex
Multiple Endocrine Neoplasia Type 1
Familial Isolated Pituitary Adenoma
Acromegaly
Computer Simulation
Polyacrylamide Gel Electrophoresis
Carcinogenesis
Nucleotides

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

Tichomirowa, M. A., Lee, M., Barlier, A., Daly, A. F., Marinoni, I., Jaffrain-Rea, M. L., ... Beckers, A. (2012). Cyclin-dependent kinase inhibitor 1B(CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. Endocrine-Related Cancer, 19(3), 233-241. https://doi.org/10.1530/ERC-11-0362

Cyclin-dependent kinase inhibitor 1B(CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. / Tichomirowa, Maria A.; Lee, Misu; Barlier, Anne; Daly, Adrian F.; Marinoni, Ilaria; Jaffrain-Rea, Marie Lise; Naves, Luciana A.; Rodien, Patrice; Rohmer, Vincent; Faucz, Fabio Rueda; Caron, Philippe; Estour, Bruno; Lecomte, Pierre; Borson-Chazot, Françoise; Penfornis, Alfred; Yaneva, Maria; Guitelman, Mirtha; Castermans, Emily; Verhaege, Catherine; Weḿeau, Jean Louis; Tabarin, Antoine; Montanãna, Carmen Fajardo; Delemer, Brigitte; Kerlan, Veronique; Sadoul, Jean Louis; Rudelli, Christine Cortet; Archambeaud, Françoise; Zacharieva, Sabine; Theodoropoulou, Marily; Brue, Thierry; Enjalbert, Alain; Bours, Vincent; Pellegata, Natalia S.; Beckers, Albert.

In: Endocrine-Related Cancer, Vol. 19, No. 3, 06.2012, p. 233-241.

Research output: Contribution to journalArticle

Tichomirowa, MA, Lee, M, Barlier, A, Daly, AF, Marinoni, I, Jaffrain-Rea, ML, Naves, LA, Rodien, P, Rohmer, V, Faucz, FR, Caron, P, Estour, B, Lecomte, P, Borson-Chazot, F, Penfornis, A, Yaneva, M, Guitelman, M, Castermans, E, Verhaege, C, Weḿeau, JL, Tabarin, A, Montanãna, CF, Delemer, B, Kerlan, V, Sadoul, JL, Rudelli, CC, Archambeaud, F, Zacharieva, S, Theodoropoulou, M, Brue, T, Enjalbert, A, Bours, V, Pellegata, NS & Beckers, A 2012, 'Cyclin-dependent kinase inhibitor 1B(CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds', Endocrine-Related Cancer, vol. 19, no. 3, pp. 233-241. https://doi.org/10.1530/ERC-11-0362
Tichomirowa, Maria A. ; Lee, Misu ; Barlier, Anne ; Daly, Adrian F. ; Marinoni, Ilaria ; Jaffrain-Rea, Marie Lise ; Naves, Luciana A. ; Rodien, Patrice ; Rohmer, Vincent ; Faucz, Fabio Rueda ; Caron, Philippe ; Estour, Bruno ; Lecomte, Pierre ; Borson-Chazot, Françoise ; Penfornis, Alfred ; Yaneva, Maria ; Guitelman, Mirtha ; Castermans, Emily ; Verhaege, Catherine ; Weḿeau, Jean Louis ; Tabarin, Antoine ; Montanãna, Carmen Fajardo ; Delemer, Brigitte ; Kerlan, Veronique ; Sadoul, Jean Louis ; Rudelli, Christine Cortet ; Archambeaud, Françoise ; Zacharieva, Sabine ; Theodoropoulou, Marily ; Brue, Thierry ; Enjalbert, Alain ; Bours, Vincent ; Pellegata, Natalia S. ; Beckers, Albert. / Cyclin-dependent kinase inhibitor 1B(CDKN1B) gene variants in AIP mutation-negative familial isolated pituitary adenoma kindreds. In: Endocrine-Related Cancer. 2012 ; Vol. 19, No. 3. pp. 233-241.
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abstract = "Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25{\%} of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A > C (p.K96Q) and c.356T > C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27 I119T shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C > T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.",
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AU - Tichomirowa, Maria A.

AU - Lee, Misu

AU - Barlier, Anne

AU - Daly, Adrian F.

AU - Marinoni, Ilaria

AU - Jaffrain-Rea, Marie Lise

AU - Naves, Luciana A.

AU - Rodien, Patrice

AU - Rohmer, Vincent

AU - Faucz, Fabio Rueda

AU - Caron, Philippe

AU - Estour, Bruno

AU - Lecomte, Pierre

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AU - Penfornis, Alfred

AU - Yaneva, Maria

AU - Guitelman, Mirtha

AU - Castermans, Emily

AU - Verhaege, Catherine

AU - Weḿeau, Jean Louis

AU - Tabarin, Antoine

AU - Montanãna, Carmen Fajardo

AU - Delemer, Brigitte

AU - Kerlan, Veronique

AU - Sadoul, Jean Louis

AU - Rudelli, Christine Cortet

AU - Archambeaud, Françoise

AU - Zacharieva, Sabine

AU - Theodoropoulou, Marily

AU - Brue, Thierry

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AB - Familial isolated pituitary adenoma (FIPA) occurs in families and is unrelated to multiple endocrine neoplasia type 1 and Carney complex. Mutations in AIP account only for 15-25% of FIPA families. CDKN1B mutations cause MEN4 in which affected patients can suffer from pituitary adenomas. With this study, we wanted to assess whether mutations in CDKN1B occur among a large cohort of AIP mutation-negative FIPA kindreds. Eighty-eight AIP mutation-negative FIPA families were studied and 124 affected subjects underwent sequencing of CDKN1B. Functional analysis of putative CDKN1B mutations was performed using in silico and in vitro approaches. Germline CDKN1B analysis revealed two nucleotide changes: c.286A > C (p.K96Q) and c.356T > C (p.I119T). In vitro, the K96Q change decreased p27 affinity for Grb2 but did not segregate with pituitary adenoma in the FIPA kindred. The I119T substitution occurred in a female patient with acromegaly. p27 I119T shows an abnormal migration pattern by SDS-PAGE. Three variants (p.S56T, p.T142T, and c.605+36C > T) are likely nonpathogenic because In vitro effects were not seen. In conclusion, two patients had germline sequence changes in CDKN1B, which led to functional alterations in the encoded p27 proteins in vitro. Such rare CDKN1B variants may contribute to the development of pituitary adenomas, but their low incidence and lack of clear segregation with affected patients make CDKN1B sequencing unlikely to be of use in routine genetic investigation of FIPA kindreds. However, further characterization of the role of CDKN1B in pituitary tumorigenesis in these and other cases could help clarify the clinicopathological profile of MEN4.

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