CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: Functional characterization of a novel CDKN2A germ line mutation

G. Della Torre, B. Pasini, S. Frigerio, R. Donghi, D. Rovini, D. Delia, G. Peters, T. J G Huot, G. Bianchi-Scarra, F. Lantieri, M. Rodolfo, G. Parmiani, M. A. Pierotti

Research output: Contribution to journalArticle

Abstract

Physical interaction between CDKN2A/p16 and CDK4 proteins regulates the cell cycle progression through the G1 phase and dysfunction of these proteins by gene mutation is implicated in genetic predisposition to melanoma. We analysed 15 Italian melanoma families for germ line mutations in the coding region of the CDKN2A gene and exon 2 of the CDK4 gene. One novel disease-associated mutation (P48T), 3 known pathological mutations (R24P, G101W and N71S) and 2 common polymorphisms (A148T and Nt500 G>C) were identified in the CDKN2A gene. In a family harbouring the R24P mutation, an intronic variant (IVS1, +37 G>C) of uncertain significance was detected in a non-carrier melanoma case. The overall incidence of CDKN2A mutations was 33.3%, but this percentage was higher in families with 3 or more melanoma cases (50%) than in those with only 2 affected relatives (25%). Noteworthy, functional analysis established that the novel mutated protein, while being impaired in cell growth and inhibition assays, retains some in vitro binding to CDK4/6. No variant in the p16-binding region of CDK4 was identified in our families. Our results, obtained in a heterogeneous group of families, support the view that inactivating mutations of CDKN2A contribute to melanoma susceptibility more than activating mutations of CDK4 and that other genetic factors must be responsible for melanoma clustering in a high proportion of families. In addition, they indicate the need for a combination of functional assays to determine the pathogenetic nature of new CDKN2A mutations.

Original languageEnglish
Pages (from-to)836-844
Number of pages9
JournalBritish Journal of Cancer
Volume85
Issue number6
DOIs
Publication statusPublished - Sep 14 2001

Fingerprint

Germ-Line Mutation
Melanoma
Mutation
p16 Genes
Cell Cycle Proteins
G1 Phase
Genetic Predisposition to Disease
Cluster Analysis
Exons
Proteins
Incidence
Growth

Keywords

  • CDKN2A and CDK4 genes
  • Familial melanoma
  • Germ line mutations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families : Functional characterization of a novel CDKN2A germ line mutation. / Torre, G. Della; Pasini, B.; Frigerio, S.; Donghi, R.; Rovini, D.; Delia, D.; Peters, G.; Huot, T. J G; Bianchi-Scarra, G.; Lantieri, F.; Rodolfo, M.; Parmiani, G.; Pierotti, M. A.

In: British Journal of Cancer, Vol. 85, No. 6, 14.09.2001, p. 836-844.

Research output: Contribution to journalArticle

Torre, GD, Pasini, B, Frigerio, S, Donghi, R, Rovini, D, Delia, D, Peters, G, Huot, TJG, Bianchi-Scarra, G, Lantieri, F, Rodolfo, M, Parmiani, G & Pierotti, MA 2001, 'CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: Functional characterization of a novel CDKN2A germ line mutation', British Journal of Cancer, vol. 85, no. 6, pp. 836-844. https://doi.org/10.1054/bjoc.2001.1991
Torre, G. Della ; Pasini, B. ; Frigerio, S. ; Donghi, R. ; Rovini, D. ; Delia, D. ; Peters, G. ; Huot, T. J G ; Bianchi-Scarra, G. ; Lantieri, F. ; Rodolfo, M. ; Parmiani, G. ; Pierotti, M. A. / CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families : Functional characterization of a novel CDKN2A germ line mutation. In: British Journal of Cancer. 2001 ; Vol. 85, No. 6. pp. 836-844.
@article{e42d4873a805456383c59244e004238d,
title = "CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families: Functional characterization of a novel CDKN2A germ line mutation",
abstract = "Physical interaction between CDKN2A/p16 and CDK4 proteins regulates the cell cycle progression through the G1 phase and dysfunction of these proteins by gene mutation is implicated in genetic predisposition to melanoma. We analysed 15 Italian melanoma families for germ line mutations in the coding region of the CDKN2A gene and exon 2 of the CDK4 gene. One novel disease-associated mutation (P48T), 3 known pathological mutations (R24P, G101W and N71S) and 2 common polymorphisms (A148T and Nt500 G>C) were identified in the CDKN2A gene. In a family harbouring the R24P mutation, an intronic variant (IVS1, +37 G>C) of uncertain significance was detected in a non-carrier melanoma case. The overall incidence of CDKN2A mutations was 33.3{\%}, but this percentage was higher in families with 3 or more melanoma cases (50{\%}) than in those with only 2 affected relatives (25{\%}). Noteworthy, functional analysis established that the novel mutated protein, while being impaired in cell growth and inhibition assays, retains some in vitro binding to CDK4/6. No variant in the p16-binding region of CDK4 was identified in our families. Our results, obtained in a heterogeneous group of families, support the view that inactivating mutations of CDKN2A contribute to melanoma susceptibility more than activating mutations of CDK4 and that other genetic factors must be responsible for melanoma clustering in a high proportion of families. In addition, they indicate the need for a combination of functional assays to determine the pathogenetic nature of new CDKN2A mutations.",
keywords = "CDKN2A and CDK4 genes, Familial melanoma, Germ line mutations",
author = "Torre, {G. Della} and B. Pasini and S. Frigerio and R. Donghi and D. Rovini and D. Delia and G. Peters and Huot, {T. J G} and G. Bianchi-Scarra and F. Lantieri and M. Rodolfo and G. Parmiani and Pierotti, {M. A.}",
year = "2001",
month = "9",
day = "14",
doi = "10.1054/bjoc.2001.1991",
language = "English",
volume = "85",
pages = "836--844",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - CDKN2A and CDK4 mutation analysis in Italian melanoma-prone families

T2 - Functional characterization of a novel CDKN2A germ line mutation

AU - Torre, G. Della

AU - Pasini, B.

AU - Frigerio, S.

AU - Donghi, R.

AU - Rovini, D.

AU - Delia, D.

AU - Peters, G.

AU - Huot, T. J G

AU - Bianchi-Scarra, G.

AU - Lantieri, F.

AU - Rodolfo, M.

AU - Parmiani, G.

AU - Pierotti, M. A.

PY - 2001/9/14

Y1 - 2001/9/14

N2 - Physical interaction between CDKN2A/p16 and CDK4 proteins regulates the cell cycle progression through the G1 phase and dysfunction of these proteins by gene mutation is implicated in genetic predisposition to melanoma. We analysed 15 Italian melanoma families for germ line mutations in the coding region of the CDKN2A gene and exon 2 of the CDK4 gene. One novel disease-associated mutation (P48T), 3 known pathological mutations (R24P, G101W and N71S) and 2 common polymorphisms (A148T and Nt500 G>C) were identified in the CDKN2A gene. In a family harbouring the R24P mutation, an intronic variant (IVS1, +37 G>C) of uncertain significance was detected in a non-carrier melanoma case. The overall incidence of CDKN2A mutations was 33.3%, but this percentage was higher in families with 3 or more melanoma cases (50%) than in those with only 2 affected relatives (25%). Noteworthy, functional analysis established that the novel mutated protein, while being impaired in cell growth and inhibition assays, retains some in vitro binding to CDK4/6. No variant in the p16-binding region of CDK4 was identified in our families. Our results, obtained in a heterogeneous group of families, support the view that inactivating mutations of CDKN2A contribute to melanoma susceptibility more than activating mutations of CDK4 and that other genetic factors must be responsible for melanoma clustering in a high proportion of families. In addition, they indicate the need for a combination of functional assays to determine the pathogenetic nature of new CDKN2A mutations.

AB - Physical interaction between CDKN2A/p16 and CDK4 proteins regulates the cell cycle progression through the G1 phase and dysfunction of these proteins by gene mutation is implicated in genetic predisposition to melanoma. We analysed 15 Italian melanoma families for germ line mutations in the coding region of the CDKN2A gene and exon 2 of the CDK4 gene. One novel disease-associated mutation (P48T), 3 known pathological mutations (R24P, G101W and N71S) and 2 common polymorphisms (A148T and Nt500 G>C) were identified in the CDKN2A gene. In a family harbouring the R24P mutation, an intronic variant (IVS1, +37 G>C) of uncertain significance was detected in a non-carrier melanoma case. The overall incidence of CDKN2A mutations was 33.3%, but this percentage was higher in families with 3 or more melanoma cases (50%) than in those with only 2 affected relatives (25%). Noteworthy, functional analysis established that the novel mutated protein, while being impaired in cell growth and inhibition assays, retains some in vitro binding to CDK4/6. No variant in the p16-binding region of CDK4 was identified in our families. Our results, obtained in a heterogeneous group of families, support the view that inactivating mutations of CDKN2A contribute to melanoma susceptibility more than activating mutations of CDK4 and that other genetic factors must be responsible for melanoma clustering in a high proportion of families. In addition, they indicate the need for a combination of functional assays to determine the pathogenetic nature of new CDKN2A mutations.

KW - CDKN2A and CDK4 genes

KW - Familial melanoma

KW - Germ line mutations

UR - http://www.scopus.com/inward/record.url?scp=0035860135&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035860135&partnerID=8YFLogxK

U2 - 10.1054/bjoc.2001.1991

DO - 10.1054/bjoc.2001.1991

M3 - Article

C2 - 11556834

AN - SCOPUS:0035860135

VL - 85

SP - 836

EP - 844

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 6

ER -