Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma

Ling Liu, Norman J. Lassam, Joyce M. Slingerland, Denis Bailey, David Cole, Robert Brian Jenkins, David Hogg

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.

Original languageEnglish (US)
Pages (from-to)404-412
Number of pages9
JournalOncogene
Volume11
Issue number2
StatePublished - Jul 20 1995

Fingerprint

Cyclin-Dependent Kinase Inhibitor p16
p16 Genes
Germ-Line Mutation
Melanoma
Alleles
cdc Genes
Mutation
Human Chromosomes
Mutant Proteins
Genes
Exons
Embryonic Structures
Fibroblasts
Amino Acids
Neoplasms
Proteins

Keywords

  • cdk inhibitors
  • Melanoma
  • p16

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Liu, L., Lassam, N. J., Slingerland, J. M., Bailey, D., Cole, D., Jenkins, R. B., & Hogg, D. (1995). Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. Oncogene, 11(2), 404-412.

Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. / Liu, Ling; Lassam, Norman J.; Slingerland, Joyce M.; Bailey, Denis; Cole, David; Jenkins, Robert Brian; Hogg, David.

In: Oncogene, Vol. 11, No. 2, 20.07.1995, p. 404-412.

Research output: Contribution to journalArticle

Liu, L, Lassam, NJ, Slingerland, JM, Bailey, D, Cole, D, Jenkins, RB & Hogg, D 1995, 'Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma', Oncogene, vol. 11, no. 2, pp. 404-412.
Liu L, Lassam NJ, Slingerland JM, Bailey D, Cole D, Jenkins RB et al. Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. Oncogene. 1995 Jul 20;11(2):404-412.
Liu, Ling ; Lassam, Norman J. ; Slingerland, Joyce M. ; Bailey, Denis ; Cole, David ; Jenkins, Robert Brian ; Hogg, David. / Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma. In: Oncogene. 1995 ; Vol. 11, No. 2. pp. 404-412.
@article{ac9c368b798c47c9bb547e6d8ad3661e,
title = "Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma",
abstract = "The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.",
keywords = "cdk inhibitors, Melanoma, p16",
author = "Ling Liu and Lassam, {Norman J.} and Slingerland, {Joyce M.} and Denis Bailey and David Cole and Jenkins, {Robert Brian} and David Hogg",
year = "1995",
month = "7",
day = "20",
language = "English (US)",
volume = "11",
pages = "404--412",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma

AU - Liu, Ling

AU - Lassam, Norman J.

AU - Slingerland, Joyce M.

AU - Bailey, Denis

AU - Cole, David

AU - Jenkins, Robert Brian

AU - Hogg, David

PY - 1995/7/20

Y1 - 1995/7/20

N2 - The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.

AB - The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.

KW - cdk inhibitors

KW - Melanoma

KW - p16

UR - http://www.scopus.com/inward/record.url?scp=0028981664&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028981664&partnerID=8YFLogxK

M3 - Article

C2 - 7624155

AN - SCOPUS:0028981664

VL - 11

SP - 404

EP - 412

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 2

ER -