Cyclin D1 gene (CCND1) mutations in endometrial cancer.
Cyclin D1 is frequently overexpressed in human neoplasias by gene rearrangement and amplification, but no mutations in the CCND1 gene have so far been reported. However, in vitro mutagenesis of CCND1 has shown that substitutions affecting threonine 286 residue produced cyclin D1 nuclear accumulation, by interfering with protein degradation and induced neoplastic transformation in murine fibroblasts. To test whether similar genetic changes may occur in vivo, we analysed a series of 60 endometrioid endometrial carcinomas (EECs) for cyclin D1 expression and gene amplification by immunohistochemistry and FISH, respectively. Two of 17 carcinomas showing cyclin D1 expression in more than 5% of neoplastic cells, but without gene amplification, were found to harbor single-base substitutions in CCND1 that changed proline 287 into threonine and serine, respectively. Both cases expressed cyclin D1 in more than 50% of neoplastic cells. Additionally, seven tumors with cyclin D1 overexpression of an independent series of 59 EECs were also analysed, and a 12-bp in-frame deletion that eliminated amino acids 289-292 was detected in one case with cylin D1 expression in more than 50% of neoplastic cells. In contrast, no mutations of the CCND1 gene were detected in a set of breast carcinomas with cyclin D1 overexpression without gene amplification. In summary, our data indicate that mutations of CCND1, which probably render the protein insensitive to degradation, represent a previously unreported mechanism of cyclin D1 overexpression in human tumors in vivo.
Moreno-Bueno
Gema
G
Laboratory of Breast and Gynaecological Cancer, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Rodríguez-Perales
Sandra
S
Sánchez-Estévez
Carolina
C
Hardisson
David
D
Sarrió
David
D
Prat
Jaime
J
Cigudosa
Juan C
JC
Matias-Guiu
Xavier
X
Palacios
José
J
D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D009154:Mutation; D012680:Sensitivity and Specificity
D019938:Cyclin D1