Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia

G. Occhi, G. Trivellin, F. Ceccato, P. De Lazzari, G. Giorgi, S. Demattè, F. Grimaldi, R. Castello, M. V. Davì, G. Arnaldi, L. Salviati, G. Opocher, F. Mantero, C. Scaroni

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27KIP1 encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors. Methods: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated. Results: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49±18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families. Conclusion: AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27KIP1 is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.

Original languageEnglish
Pages (from-to)369-376
Number of pages8
JournalEuropean Journal of Endocrinology
Volume163
Issue number3
DOIs
Publication statusPublished - Sep 1 2010

Fingerprint

Multiple Endocrine Neoplasia
Mutation
Pituitary Neoplasms
Genes
Multiple Endocrine Neoplasia Type 1
Prolactinoma
Neoplasms
Acromegaly
Germ-Line Mutation
Heterozygote
Point Mutation
Prolactin
Virulence
Familial Isolated Pituitary Adenoma
DNA

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia. / Occhi, G.; Trivellin, G.; Ceccato, F.; De Lazzari, P.; Giorgi, G.; Demattè, S.; Grimaldi, F.; Castello, R.; Davì, M. V.; Arnaldi, G.; Salviati, L.; Opocher, G.; Mantero, F.; Scaroni, C.

In: European Journal of Endocrinology, Vol. 163, No. 3, 01.09.2010, p. 369-376.

Research output: Contribution to journalArticle

Occhi, G, Trivellin, G, Ceccato, F, De Lazzari, P, Giorgi, G, Demattè, S, Grimaldi, F, Castello, R, Davì, MV, Arnaldi, G, Salviati, L, Opocher, G, Mantero, F & Scaroni, C 2010, 'Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia', European Journal of Endocrinology, vol. 163, no. 3, pp. 369-376. https://doi.org/10.1530/EJE-10-0327
Occhi, G. ; Trivellin, G. ; Ceccato, F. ; De Lazzari, P. ; Giorgi, G. ; Demattè, S. ; Grimaldi, F. ; Castello, R. ; Davì, M. V. ; Arnaldi, G. ; Salviati, L. ; Opocher, G. ; Mantero, F. ; Scaroni, C. / Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia. In: European Journal of Endocrinology. 2010 ; Vol. 163, No. 3. pp. 369-376.
@article{99202683c8fe4196bc066665b68c5cea,
title = "Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia",
abstract = "Background: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27KIP1 encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors. Methods: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated. Results: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1{\%}) with relatively high age at diagnosis (49±18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families. Conclusion: AIP is mutated in about 3{\%} of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27KIP1 is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.",
author = "G. Occhi and G. Trivellin and F. Ceccato and {De Lazzari}, P. and G. Giorgi and S. Dematt{\`e} and F. Grimaldi and R. Castello and Dav{\`i}, {M. V.} and G. Arnaldi and L. Salviati and G. Opocher and F. Mantero and C. Scaroni",
year = "2010",
month = "9",
day = "1",
doi = "10.1530/EJE-10-0327",
language = "English",
volume = "163",
pages = "369--376",
journal = "European Journal of Endocrinology",
issn = "0804-4643",
publisher = "BioScientifica Ltd.",
number = "3",

}

TY - JOUR

T1 - Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia

AU - Occhi, G.

AU - Trivellin, G.

AU - Ceccato, F.

AU - De Lazzari, P.

AU - Giorgi, G.

AU - Demattè, S.

AU - Grimaldi, F.

AU - Castello, R.

AU - Davì, M. V.

AU - Arnaldi, G.

AU - Salviati, L.

AU - Opocher, G.

AU - Mantero, F.

AU - Scaroni, C.

PY - 2010/9/1

Y1 - 2010/9/1

N2 - Background: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27KIP1 encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors. Methods: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated. Results: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49±18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families. Conclusion: AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27KIP1 is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.

AB - Background: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27KIP1 encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors. Methods: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated. Results: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49±18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families. Conclusion: AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27KIP1 is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.

UR - http://www.scopus.com/inward/record.url?scp=77956297046&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956297046&partnerID=8YFLogxK

U2 - 10.1530/EJE-10-0327

DO - 10.1530/EJE-10-0327

M3 - Article

C2 - 20530095

AN - SCOPUS:77956297046

VL - 163

SP - 369

EP - 376

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

SN - 0804-4643

IS - 3

ER -