Summary
The roles of the p16 and p15 inhibitor of cyclin-dependent kinase tumour suppressor genes were examined in human uterine cervical and endometrial cancers. p16 mRNA, examined by reverse transcription polymerase chain reaction (RT-PCR), was significantly reduced in five of 19 (26%) cervical and four of 25 (16%) endometrial tumours. Reduced expression of p16 protein, detected by immunohistochemistry, occurred even more frequently, in nine of 33 (27%) cervical and seven of 37 (19%) endometrial tumours. Hypermethylation of a site within the 5′-CpG island of the p16 gene was detected in only one of 32 (3%) cervical tumours and none of 26 endometrial tumours. Homozygous p16 gene deletion, evaluated by differential PCR analysis, was found in four of 40 (10%) cervical tumours and one of 38 (3%) endometrial tumours. Homozygous deletion of p15 was found in three of 40 (8%) cervical tumours and one of 38 (3%) endometrial tumours. PCR-SSCP (single-strand conformation polymorphism) analysis detected point mutations in the p16 gene in six (8%) of 78 uterine tumours (four of 40 (10%) cervical tumours and two of 38 (5%) endometrial tumours). Three were mis-sense mutations, one in codon 74 (CTG→ATG) and one in codon 129 (ACC→ATC), both in cervical carcinomas, and the other was in codon 127 (GGG→GAG) in an endometrial carcinoma. There was one non-sense mutation, in codon 50 (CGA→TGA), in an endometrial carcinoma. The remaining two were silent somatic cell mutations, both in cervical carcinomas, resulting in no amino acid change. These observations suggest that inactivation of the p16 gene, either by homologous deletion, mutation or loss of expression, occurs in a subset of uterine tumours.
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References
Enomoto, T., Weghorst, C. M., Inoue, M., Tanizawa, O. & Rice, J. M. (1991). K-ras activation occurs frequently in mucinous adenocarcinomas and rarely in other common epithelial tumors of the human ovary. Am J Pathol 139: 777–785.
Enomoto, T., Fujita, M., Inoue, M., Rice, J. M., Nakajima, R., Tanizawa, O. & Nomura, T. (1993). Alterations of the p53 tumor suppressor gene and its association with activation of the c-K-ras-2 protooncogene in premalignant and malignant lesions of the human uterine endometrium. Cancer Res 53: 1883–1888.
Foulkes, W. D., Flanders, T. Y., Pollock, P. M. & Hayward, N. K. (1997). The CDKN2A (p16) gene and human cancer. Mol Med 3: 5–20.
Fujita, M., Inoue, M., Tanizawa, O., Iwamoto, S. & Enomoto, T. (1992). Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection. Cancer Res 52: 5323–5328.
Fuqua, S. A. W., Falette, N. F. & McGuire, W. L. (1990). Sensitive detection of estrogen receptor RNA by polymerase chain reaction assay. J Natl Cancer Inst 82: 858–861.
Gonzalez-Zulueta, M., Bender, C. M., Yang, A. S., Nguyen, T. W., Beart, R., Van Tornout, J. M. & Jones, P. A. (1995). Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res 55: 4531–4535.
Guan, K-L, Jenkins, C. W., Li, Y., Nichols, M. A., Wu, X., O’Keefe, C. L., Matera, A. G. & Xiong, Y. (1994). Growth suppression by p18, a p16INK4/MTS1-and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function. Genes Dev 8: 2939–2952.
Hannon, G. J. & Beach, D. (1994). p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature (Lond) 371: 257–261.
Hatta, Y., Hirama, T., Takeuchi, S., Lee, E., Pham, E., Miller, C. W., Strohmeyer, T., Wilczynski, S. P., Melmed, S. & Koeffler, H. P. (1995). Alterations of the p16 (MTS1) gene in testicular, ovarian, and endometrial malignancies. J Urol 154: 1954–1957.
Hengstschläger, M., Hengstschläger-Ottnad, E., Pusch, O. & Wawra, E. (1996). The role of p16 in the E2F-dependent thymidine kinase regulation. Oncogene 12: 1635–1643.
Herman, J. G., Jen, J., Merlo, A. & Baylin, S. B. (1996). Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res 56: 722–727.
Herman, J. G., Merlo, A., Mao, L., Lapidus, R. G., Issa, J-PJ, Davidson, N. E., Sidransky, D. & Baylin, S. B. (1995). Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525–4530.
Hirama, T., Miller, C. W., Wilczynski, S. P. & Koeffler, H. P. (1996). p16 (CDKN2/cyclin-dependent kinase-4 inhibitor/multiple tumor suppressor-1) gene is not altered in uterine cervical carcinomas or cell lines. Modern Pathol 9: 26–31.
Jen, J., Harper, J. W., Bigner, S. H., Bigner, D. D., Papadopoulos, N., Markowitz, S., Willson, J. K. V., Kinzler, K. W. & Vogelstein, B. (1994). Detection of p16 and p15 genes in brain tumors. Cancer Res 54: 6353–6358.
Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, RSIII, Johnson, B. E. & Skolnick, M. H. (1994). A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436–440.
Kelly, M. J., Otterson, G. A., Kaye, F. J., Popescu, N. C., Johnson, B. E. & Dipaulo, J. A. (1995). CDKN2 in HPV-positive and HPV-negative cervical-carcinoma cell lines. Int J Cancer 63: 226–230.
Kim, J. W., Namkoong, S. E., Ryu, S. W., Kim, H. S., Shin, J. W., Lee, J. M., Kim, D. H. & Kim, I. K. (1998). Absence of p15(INK4B) and p16(INK4A) gene alterations in primary cervical carcinoma tissues and cell lines with human papillomavirus infection. Gynecol Oncol 70: 75–79.
Lo, K-W, Cheung, S-T, Leung, S-F, Van Hasselt, A., Tsang, Y-S, Mak, K-F, Chung, Y-F, Woo, J. K. S., Lee, J. C. K. & Huang, D. P. (1996). Hypermethylation of the p16 gene in nasopharyngeal carcinoma. Cancer Res 56: 2721–2725.
Lu, X., Toki, T., Konishi, I., Nikaido, T. & Fujii, S. (1998). Expression of p21WAF1/CIP1 in adenocarcinoma of the uterine cervix: a possible immunohistochemical marker of a favorable prognosis. Cancer 82: 2409–2417.
Lukas, J., Otzen Petersen, B., Holm, K., Bartek, J. & Helin, K. (1996). Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression. Mol Cell Biol 16: 1047–1057.
Marchetti, A., Buttitta, F., Pellegrini, S., Bertacca, G., Chella, A., Carnicelli, V., Tognoni, V., Filardo, A., Angeletti, A. & Bevilacqua, G. (1997). Alterations of p16 (MTS1) in node-positive non-small cell lung carcinomas. J Pathol 181: 178–182.
Merlo, A., Herman, J. G., Mao, L., Lee, D. J., Gabrielson, E., Burger, P. C., Baylin, S. B. & Sidransky, D. (1995). 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med 1: 686–692.
Munirajan, A. K., Kannan, K., Bhuvarahamurthy, V., Ishida, I., Fujinaga, K., Tsuchida, N. & Shanmugam, G. (1998). The status of human papillomavirus and tumor suppressor genes p53 and p16 in carcinomas of uterine cervix from India. Gynecol Oncol 69: 205–209.
Nobori, T., Miura, K., Wu, D. J., Lois, A., Takabayashi, K. & Carson, D. A. (1994). Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature (Lond) 368: 753–756.
Owen, D. & Küehn, L. C. (1987). Noncoding 3′ sequences of the transferrin receptor gene are required for mRNA regulation by iron. EMBO J 6: 1287–1293.
Parker, M. F., Arroyo, G. F., Geradts, J., Sabichi, A. L., Park, R. C., Taylor, R. R. & Birrer, M. J. (1997). Molecular characterization of adenocarcinoma of the cervix. Gynecol Oncol 64: 242–251.
Peiffer, S. L., Bartsch, D., Whelan, A. J., Mutch, D. G., Herzog, T. J. & Goodfellow, P. J. (1995). Low frequency of CDKN2 mutation in endometrial carcinomas. Mol Carcinog 13: 210–212.
Pollock, P. M., Pearson, J. V. & Hayward, N. K. (1996). Compilation of somatic mutations of the CDKN2 gene in human cancers, non-random distribution of base substitutions. Gene Chromosomes Cancer 15: 77–88.
Serrano, M., Haanon, G. J. & Beach, D. (1993). A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature (Lond) 366: 704–707.
Sheffield, V. C., Beck, J. S., Kwitek, A. E., Sandstrom, D. W. & Stone, E. M. (1993). The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics 16: 325–332.
Shiozawa, T., Nikaido, T., Shimizu, M., Zhai, Y. & Fujii, S. (1997). Immunohistochemical analysis of the expression of cdk4 and p16INK4 in human endometrioid-type endometrial carcinoma. Cancer 80: 2250–2256.
Stone, S., Jiang, P., Dayananth, P., Tavtigian, S. V., Katcher, H., Parry, D., Peters, G. & Kamb, A. (1995). Complex structure and regulation of the p16 (MTS1) locus. Cancer Res 55: 2988–2994.
Washimi, O., Nagatake, M., Osada, H., Ueda, R., Koshikawa, T., Seki, T., Takahashi, T. & Takahashi, T. (1995). In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. Cancer Res 55: 514–517.
Wong, Y. F., Chung, T. K. H., Cheung, T. H., Nobori, T., Yim, S. F., Lai, K. W. H., Yu, A. L., Diccianni, M. B., Li, T. Z. & Chang, A. M. Z. (1997). p16INK4 and p15INK4B alterations in primary gynecologic malignancy. Gynecol Oncol 65: 319–324.
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Nakashima, R., Fujita, M., Enomoto, T. et al. Alteration of p16 and p15 genes in human uterine tumours. Br J Cancer 80, 458–467 (1999). https://doi.org/10.1038/sj.bjc.6690379
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DOI: https://doi.org/10.1038/sj.bjc.6690379
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