Abstract
The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21–p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/ insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
206,07 € per year
only 17,17 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Boring, C.C., Squires, T.S. & Tong, T. Cancer statistics, 1993. CA Cancer J. Clin. 43, 7–26 (1993).
Almoguerra, C. et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53, 549–554 (1988).
Hruban, R.H. et al. K-ras oncogene activation in adenocarcinomas of the human pancreas: a study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotlde hybridization. Am. J. Pathol. 143, 545–554 (1993).
Pellegata, S. et al. K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res. 54, 1556–1560 (1994).
Redston, M.S. et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopoiymer tracts in DNA microdeletions. Cancer Res. 54, 3025–3033 (1994).
Seymour, A.B. et al. Allelotype of pancreatic adenocarcinoma. Cancer Res. 54, 2761–2764 (1994).
El-Deiry, W. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).
Noda, A., Ning, Y., Venable, S.F., Pereira-Smith, O.M. & Smith, J.R. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp. Cell Res. 211, 90–98 (1994).
Xiong, Y. et al. p21 is a universal inhibitor of cyclin kinases. Nature 366, 701–707 (1993).
Harper, J.W., Adami, G.R., Wei, N., Keyomarsi, K. & Elledge, S.J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyciin-dependent kinases. Cell 75, 805–816 (1993).
Serrano, M., Hannon, G.J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).
Kamb, A. et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436–440 (1994).
Nobori, T. et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368, 753–756 (1994).
Cannon-Albright, L.A. et al. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13–p22. Science 258, 1148–1152 (1992).
Bos, J.L. et al. Prevalence of ras gene mutations in human colorectal cancers. Nature 327, 293–297 (1987).
Weber, J.L. & May, P.E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am. J. hum. Genet. 44, 388–396 (1989).
Kwaitkowski, K.W., Armour, J., Bale, A.E., Fountain, J.W. & Goudie, D. Report on the second international workshop on hyman chromosome 9. Cytogenet. Cell Genet. 64, 94–103 (1993).
Okamoto, A. et al. Mutations and altered expression of p16INK4 in human cancer. Proc. natn. Acad. Sci. U.S.A. (in the press).
Cairns, P. et al. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science 265, 415–416 (1994).
Spruck, C.H. III et al. p16 gene in uncultured tumours. Nature 370, 183–184 (1994).
Yanagisawa, A. et al. Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res. 53, 953–956 (1993).
Caldas, C. et al. Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res. 54, 3568–3573 (1994).
Cameron, J.L. et al. Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer. Am. J. Surg. 161, 120–125 (1991).
Feinberg, A.P. & Vogelstein, B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 137, 266–267 (1984).
Ruggeri, B. et al. Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and Rb-1 tumor-suppressor genes. Oncogene 7, 1503–1511 (1992).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Caldas, C., Hahn, S., da Costa, L. et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8, 27–32 (1994). https://doi.org/10.1038/ng0994-27
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0994-27
