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Hemizygous or homozygous deletion of the chromosomal region containing the p16 INK4a gene is associated with amplification of the EGF receptor gene in glioblastomas
Author(s) -
Hegi Monika E.,
zur Hausen Axel,
Rüedi Daniela,
Malin Gerhard,
Kleihues Paul
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970926)73:1<57::aid-ijc10>3.0.co;2-2
Subject(s) - biology , cancer research , locus (genetics) , cyclin dependent kinase , gene silencing , gene , microbiology and biotechnology , gene dosage , tumor suppressor gene , cell cycle , gene expression , genetics , carcinogenesis
The p16 INK4a gene product acts as a negative regulator of the cell cycle by binding to cyclin‐dependent kinases (CDKs) 4 and 6, thereby inhibiting the formation of an active CDK/cyclin D complex. Deletion of the p16 locus has been observed in tumor cell lines and, less frequently, in primary human neoplasms. We analyzed 31 glioblastomas and identified 6 cases with hemizygous and 6 with homozygous deletions of the p16 locus. Eight of these cases showed a concurrent amplification of the EGFR gene (epidermal growth factor receptor) while the overall frequency was 35%. This close correlation suggests that deletion of the p16 chromosomal region constitutes another genetic hallmark of the primary glioblastoma, which rapidly develops de novo, without a less malignant precursor lesion and for which EGFR amplification is a characteristic genetic change. The p16 protein was not detectable in 15 of 22 glioblastomas but only 4 of these showed homozygous deletion of the gene. The alternative transcript p16β, for which a growth‐suppressing function has been suggested, was co‐expressed with p16α mRNA in most cases. Hypermethylation of CpG islands in the 5′ region of the p16 gene was identified in only 1 case, suggesting that this alternative mechanism of gene silencing is rarely responsible for loss of p16 expression in glioblastomas. Likewise, only 1 glioblastoma carried a p16 mutation and in addition, unexpectedly, a homozygous deletion of p16 in approximately 80% of tumor cells. This mutation, Arg24Pro, has previously been identified in a melanoma kindred. Int. J. Cancer 73:57–63, 1997. © 1997 Wiley‐Liss, Inc.