title: A novel germline CDKN1B mutation causing multiple endocrine tumors: clinical, genetic and functional characterization.
abstract: Multiple endocrine neoplasia (MEN) syndromes are characterized by tumors involving two or more endocrine glands. Two MEN syndromes have long been known: MEN1 and MEN2,caused by germline mutations in MEN1 or RET, respectively. Recently, mutations in CDKN1B,encoding the cyclin-dependent kinase (Cdk) inhibitor p27, were identified in patients having a MEN1-like phenotype but no MEN1 gene mutations. Currently, the molecular mechanisms mediating the role of p27 in tumor predisposition are ill defined. We here report a novel germline missense variant in CDKN1B (c.678C>T, p.P69L) found in a patient with multiple endocrine tumors. We previously reported a nonsense p27 mutation (c.692G>A, p.W76X) in two patients with MEN1-like phenotype. Functional assays were used to characterize p27P69L and p27W76X in vitro. We show that p27P69L is expressed at reduced level and is impaired in both binding toCdk2 and inhibiting cell growth. p27W76X, which is mislocalized to the cytoplasm, can no longer efficiently bind Cyclins-Cdks, nor inhibit cell growth or induce apoptosis. In the patient’s tumor tissues, p27P69L associates with reduced/absent p27 expression and in one tumor with loss-of heterozygosity.Our results extend previous findings of CDKN1B mutations in patients with MEN1-related states and support the hypothesis of a tumor suppressor role for p27 in neuroendocrine cells.
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Molatore
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marinoni
authors.forename: Misu
authors.initials: M
authors.lastname: Lee
authors.forename: Elke
authors.initials: E
authors.lastname: Pulz
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ambrosio
authors.forename: Ettore C
authors.initials: EC
authors.lastname: degli Uberti
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Zatelli
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
mesh_terms: D000368:Aged; D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D018095:Germ-Line Mutation; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009377:Multiple Endocrine Neoplasia / Q000145:classification / Q000235:genetics*; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C436291:CDKN1B protein, human; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D011994:Recombinant Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
references.citation: FASEB J. 2010 Aug;24(8):2998-3009
references.pmid: 20228253
references.citation: Clin Exp Allergy. 2001 Dec;31(12):1829-38
references.pmid: 11737033
references.citation: Genes Dev. 1999 Jun 15;13(12):1501-12
references.pmid: 10385618
references.citation: Cancer Res. 2008 Aug 15;68(16):6496-506
references.pmid: 18701472
references.citation: EMBO J. 2000 May 15;19(10):2168-80
references.pmid: 10811608
references.citation: Nature. 1998 Nov 12;396(6707):177-80
references.pmid: 9823898
references.citation: Cancer Res. 1997 Dec 15;57(24):5441-5
references.pmid: 9407946
references.citation: Nat Cell Biol. 1999 Aug;1(4):193-9
references.pmid: 10559916
references.citation: Int J Cancer. 2010 May 15;126(10):2362-72
references.pmid: 19876893
references.citation: Exp Cell Res. 2001 Mar 10;264(1):148-68
references.pmid: 11237531
references.citation: J Clin Endocrinol Metab. 2009 May;94(5):1826-34
references.pmid: 19141585
references.citation: Cancer Cell. 2008 Jul 8;14(1):23-35
references.pmid: 18598941
references.citation: Mol Biol Cell. 2003 Jan;14(1):201-13
references.pmid: 12529437
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15558-63
references.pmid: 17030811
references.citation: Nat Cell Biol. 2004 Dec;6(12):1229-35
references.pmid: 15531880
references.citation: Science. 1995 Aug 4;269(5224):682-5
references.pmid: 7624798
references.citation: J Clin Endocrinol Metab. 2007 Aug;92(8):3321-5
references.pmid: 17519308
references.citation: Nat Med. 1997 Feb;3(2):231-4
references.pmid: 9018245
references.citation: Mol Cell Biol. 2003 Jun;23(11):3735-52
references.pmid: 12748278
references.citation: Nature. 1996 Jul 25;382(6589):325-31
references.pmid: 8684460
references.citation: Nat Rev Cancer. 2008 Apr;8(4):253-67
references.pmid: 18354415