Abstract
The tumor suppressor genesp53, retinoblastoma (RB), p16, andp15 encode proteins that regulate the cell cycle cooperatively by controlling the transition from G1 to S phase and may play an important role in cell growth and differentiation. To screen for abnormalities in these genes in cancer, we performed genetic analysis in six human pancreatic cancer and five hepatoma cell lines, by single-strand conformation polymorphism (SSCP) analysis, direct sequencing, and the reverse transcriptase-polymerase chain reaction (RT-PCR). All six pancreatic cancer cell lines hadp53 mutations, with the concomitant loss of the other normal allele, encoding wild-typep53. Frequent homozygous deletions were found inp16 andp15, but theRB gene was expressed. Four of the five hepatoma cell lines hadp53 mutations with loss of the normal allele and aberrantRB. There were no deletions ofp16 andp15 in any of the hepatoma cell lines. These findings suggest that alterations in thep53, p16, andp15 genes are common in human pancreatic cancer cell lines, whilep53 orRB mutations are common in hepatoma cell lines. Alterations of these tumor suppressor genes may thus be important features in organ-specific carcinogenesis.
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References
Bishop JM. Molecular themes In oncogenesis. Cell 1991;64:235–248.
Yokota J, Sugimura T. Multiple steps in carcinogenesis involving alterations of multiple tumor suppressor genes. FASEB J 1993;7:920–925.
Taya Y.p53 and the RB protein connected by Cdk-inhibitory proteins. In: Ebashi S, Ohno S (eds)p53 and Cdk-inhibitory proteins. Experimental Medicine. Tokyo: Yodosha, 1995;17–18.
Levine AJ, Momand J, Finlay CA. Thep53 tumour suppressor gene. Nature 1991;351:453–456.
Nigro JM, Baker SJ, Preisinger AC, et al. Mutations in thep53 gene occur in diverse human tumour types. Nature 1989;342:705–708.
Horowitz JM, Park SH, Bogenmamann E, et al. Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci 1990;87:2775–2779.
Nobori T, Miura K, Wu DJ, et al. Deletions of thecyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994;368:753–756.
Mori T, Miura K, Aoki T, et al. Frequent somatic mutation of theMTS1/CDK4I gene in esophageal squamous cell carcinoma. Jpn J Cancer Res 1994;54:3996–3997.
Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of thep16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994;8:27–32.
Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science 1994;264:436–440.
Yoshida S, Todoroki T, Ichikawa Y, et al. Mutations of p16INK4/CDKN2 and p15INK4B/MTS2 genes in biliary tract cancers. Cancer Res 1995;55:2756–2760.
Jen J, Harper W, Bigner SH, et al. Deletion ofp16 and p15 genes in brain tumors. Cancer Res 1994;54:6353–6358.
Murakami Y, Hayashi K, Hirohashi S, et al. Aberrations of the tumor suppressorp53 andretinoblastoma genes in human hepatocellular carcinomas. Cancer Res 1991;51:5520–5525.
McGee TL, Yandell DW, Dryja TP. Structure and partial genomic sequence of the humanretinoblastoma susceptibility gene. Gene 1989;80:119–128.
Hruban RH, van Mansfeld ADM, Offerhaus GJA, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. Am J Pathol 1993;143:545–554.
Barton CM, Staddon SL, Hughes CM, et al. Abnormalities of thep53 tumour suppressor gene in human pancreatic cancer. Br J Cancer 1991;64:1076–1082.
Scarpa A, Capelli P, Mukai K, et al. Pancreatic adenocarcinomas frequently showp53 gene mutations. Am J Pathol 1993;142:1534–1543.
Berrozpe G, Schaeffer J, Peinado MA, et al. Comparative analysis of mutations in thep53 and K-ras genes in pancreatic cancer. Int J Cancer 1994;58:185–191.
Suwa H, Yoshimura T. Yamaguchi N, et al. K-ras andp53 alterations in genomic DNA and transcripts of human pancreatic adenocarcinoma cell lines. Jpn J Cancer Res 1994;85:1005–1014.
Cesarman E, Inghiram G, Chadburn A, et al. High levels ofp53 protein expression do not correlate withp53 mutations in anaplastic large cell lymphoma. Am J Pathol 1993;3:845–856.
Bourdon JC, D'errico A, Paterlini P, et al.p53 protein and accumulation in European hepatocellular carcinoma is not always dependent onp53 gene mutation. Gastroenterology 1995; 108:1176–1182.
Ruggeri B, Zhang SY, Caamano J, et al. Human pancreatic carci-nomas and cell lines reveal frequent and multiple alterations in thep53 andRb-1 tumor-suppressor genes. Oncogene 1992; 7:1503–1511.
Cairns P, Mao L, Merlo A, et al. Rates ofp16(MTS1) mutations in primary tumors with 9p loss. Science 1994;265:415–416.
Spruck C, Gonzalez-Zuleta M, Shibata A, et al.p16 gene in uncultured tumours. Nature 1994;370:183–184.
Nishida N, Fukuda Y, Kokuryu H, et al. Accumulation of allelic loss of arms of chromosomes 13q, 16q and 17p in the advanced stages of human hepatocellular carcinoma. Int J Cancer 1992;51:862–868.
Fujimori M, Tokino T, Hino O, et al. Allelotype study of primary hepatocellular carcinoma. Cancer Res 1991;51:89–93.
Puisieux A, Galvin K, Troalen F, et al.Retinoblastoma andp53 tumor suppressor genes in human hepatoma cell lines. FASEB J 1993;7:1407–1413.
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Kaino, M. Alterations in the tumor suppressor genesp53, RB, p16/MTS1, andp15/MTS2 in human pancreatic cancer and hepatoma cell lines. J Gastroenterol 32, 40–46 (1997). https://doi.org/10.1007/BF01213295
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DOI: https://doi.org/10.1007/BF01213295