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. 1999 Apr;80(1-2):79–86. doi: 10.1038/sj.bjc.6690505

Role of p16/MTS1, cyclin D1 and RB in primary oral cancer and oral cancer cell lines

M Sartor 1, H Steingrimsdottir 1, F Elamin 1, J Gäken 2, S Warnakulasuriya 1, M Partridge 3, N Thakker 4, N W Johnson 1, M Tavassoli 1
PMCID: PMC2363027  PMID: 10389982

Abstract

One of the most important components of G1 checkpoint is the retinoblastoma protein (pRB110). The activity of pRB is regulated by its phosphorylation, which is mediated by genes such as cyclin D1 and p16/MTS1. All three genes have been shown to be commonly altered in human malignancies. We have screened a panel of 26 oral squamous cell carcinomas (OSCC), nine premalignant and three normal oral tissue samples as well as eight established OSCC cell lines for mutations in the p16/MTS1 gene. The expression of p16/MTS1, cyclin D1 and pRB110 was also studied in the same panel. We have found p16/MTS1 gene alterations in 5/26 (19%) primary tumours and 6/8 (75%) cell lines. Two primary tumours and five OSCC cell lines had p16/MTS1 point mutations and another three primary and one OSCC cell line contained partial gene deletions. Six of seven p16/MTS1 point mutations resulted in termination codons and the remaining mutation caused a frameshift. Western blot analysis showed absence of p16/MTS1 expression in 18/26 (69%) OSCC, 7/9 (78%) premalignant lesions and 8/8 cell lines. One cell line, H314, contained a frameshift mutation possibly resulting in a truncated p16/MTS1 protein. pRB was detected in 14/25 (56%) of OSCC but only 11/14 (78%) of these contained all or some hypophosphorylated (active) pRB. In premalignant samples, 6/8 (75%) displayed pRB, and all three normal samples and eight cell lines analysed contained RB protein. p16/MTS1 protein was undetectable in 10/11 (91%) OSCCs with positive pRB. Overexpression of cyclin D1 was observed in 9/22 (41%) OSCC, 3/9 (33%) premalignant and 8/8 (100%) of OSCC cell lines. Our data suggest p16/MTS1 mutations and loss of expression to be very common in oral cancer cell lines and less frequent in primary OSCC tumours. A different pattern of p16/MTS1 mutations was observed in OSCC compared to other cancers with all the detected p16/MTS1 mutations resulting in premature termination codons or a frameshift. The RB protein was expressed in about half (44%) of OSCCs and its expression inversely correlated with p16/MTS1 expression. In conclusion, we show that abnormalities of the RB pathway are a common mechanism of oral carcinogenesis. © 1999 Cancer Research Campaign

Keywords: oral cancer, p16/MTS1, cyclin D1, retinoblastoma, G1 checkpoint

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Selected References

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  1. Andl T., Kahn T., Pfuhl A., Nicola T., Erber R., Conradt C., Klein W., Helbig M., Dietz A., Weidauer H. Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control. Cancer Res. 1998 Jan 1;58(1):5–13. [PubMed] [Google Scholar]
  2. Arap W., Knudsen E. S., Wang J. Y., Cavenee W. K., Huang H. J. Point mutations can inactivate in vitro and in vivo activities of p16(INK4a)/CDKN2A in human glioma. Oncogene. 1997 Feb 6;14(5):603–609. doi: 10.1038/sj.onc.1200870. [DOI] [PubMed] [Google Scholar]
  3. Bagchi S., Weinmann R., Raychaudhuri P. The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F. Cell. 1991 Jun 14;65(6):1063–1072. doi: 10.1016/0092-8674(91)90558-g. [DOI] [PubMed] [Google Scholar]
  4. Bartkova J., Lukas J., Müller H., Strauss M., Gusterson B., Bartek J. Abnormal patterns of D-type cyclin expression and G1 regulation in human head and neck cancer. Cancer Res. 1995 Feb 15;55(4):949–956. [PubMed] [Google Scholar]
  5. Bartkova J., Lukas J., Strauss M., Bartek J. Cyclin D1 oncoprotein aberrantly accumulates in malignancies of diverse histogenesis. Oncogene. 1995 Feb 16;10(4):775–778. [PubMed] [Google Scholar]
  6. Berenson J. R., Yang J., Mickel R. A. Frequent amplification of the bcl-1 locus in head and neck squamous cell carcinomas. Oncogene. 1989 Sep;4(9):1111–1116. [PubMed] [Google Scholar]
  7. Chellappan S. P., Hiebert S., Mudryj M., Horowitz J. M., Nevins J. R. The E2F transcription factor is a cellular target for the RB protein. Cell. 1991 Jun 14;65(6):1053–1061. doi: 10.1016/0092-8674(91)90557-f. [DOI] [PubMed] [Google Scholar]
  8. Chen P. L., Scully P., Shew J. Y., Wang J. Y., Lee W. H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell. 1989 Sep 22;58(6):1193–1198. doi: 10.1016/0092-8674(89)90517-5. [DOI] [PubMed] [Google Scholar]
  9. Cheng J. Q., Jhanwar S. C., Klein W. M., Bell D. W., Lee W. C., Altomare D. A., Nobori T., Olopade O. I., Buckler A. J., Testa J. R. p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma. Cancer Res. 1994 Nov 1;54(21):5547–5551. [PubMed] [Google Scholar]
  10. Elamin F., Steingrimsdottir H., Wanakulasuriya S., Johnson N., Tavassoli M. Prevalence of human papillomavirus infection in premalignant and malignant lesions of the oral cavity in U.K. subjects: a novel method of detection. Oral Oncol. 1998 May;34(3):191–197. doi: 10.1016/s1368-8375(97)00081-x. [DOI] [PubMed] [Google Scholar]
  11. Ewen M. E., Sluss H. K., Sherr C. J., Matsushime H., Kato J., Livingston D. M. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993 May 7;73(3):487–497. doi: 10.1016/0092-8674(93)90136-e. [DOI] [PubMed] [Google Scholar]
  12. Farrell W. E., Simpson D. J., Bicknell J. E., Talbot A. J., Bates A. S., Clayton R. N. Chromosome 9p deletions in invasive and noninvasive nonfunctional pituitary adenomas: the deleted region involves markers outside of the MTS1 and MTS2 genes. Cancer Res. 1997 Jul 1;57(13):2703–2709. [PubMed] [Google Scholar]
  13. Fountain J. W., Karayiorgou M., Ernstoff M. S., Kirkwood J. M., Vlock D. R., Titus-Ernstoff L., Bouchard B., Vijayasaradhi S., Houghton A. N., Lahti J. Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10557–10561. doi: 10.1073/pnas.89.21.10557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gonzalez-Zulueta M., Bender C. M., Yang A. S., Nguyen T., Beart R. W., Van Tornout J. M., Jones P. A. 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. 1995 Oct 15;55(20):4531–4535. [PubMed] [Google Scholar]
  15. Goodrich D. W., Lee W. H. Molecular characterization of the retinoblastoma susceptibility gene. Biochim Biophys Acta. 1993 May 25;1155(1):43–61. doi: 10.1016/0304-419x(93)90021-4. [DOI] [PubMed] [Google Scholar]
  16. Hagemeier C., Caswell R., Hayhurst G., Sinclair J., Kouzarides T. Functional interaction between the HCMV IE2 transactivator and the retinoblastoma protein. EMBO J. 1994 Jun 15;13(12):2897–2903. doi: 10.1002/j.1460-2075.1994.tb06584.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hannon G. J., Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994 Sep 15;371(6494):257–261. doi: 10.1038/371257a0. [DOI] [PubMed] [Google Scholar]
  18. Hara E., Smith R., Parry D., Tahara H., Stone S., Peters G. Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol Cell Biol. 1996 Mar;16(3):859–867. doi: 10.1128/mcb.16.3.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hunter T., Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. doi: 10.1016/0092-8674(94)90543-6. [DOI] [PubMed] [Google Scholar]
  20. Jiang W., Kahn S. M., Zhou P., Zhang Y. J., Cacace A. M., Infante A. S., Doi S., Santella R. M., Weinstein I. B. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene. 1993 Dec;8(12):3447–3457. [PubMed] [Google Scholar]
  21. Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436–440. doi: 10.1126/science.8153634. [DOI] [PubMed] [Google Scholar]
  22. Kamijo T., Zindy F., Roussel M. F., Quelle D. E., Downing J. R., Ashmun R. A., Grosveld G., Sherr C. J. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997 Nov 28;91(5):649–659. doi: 10.1016/s0092-8674(00)80452-3. [DOI] [PubMed] [Google Scholar]
  23. Koh J., Enders G. H., Dynlacht B. D., Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature. 1995 Jun 8;375(6531):506–510. doi: 10.1038/375506a0. [DOI] [PubMed] [Google Scholar]
  24. Kyomoto R., Kumazawa H., Toda Y., Sakaida N., Okamura A., Iwanaga M., Shintaku M., Yamashita T., Hiai H., Fukumoto M. Cyclin-D1-gene amplification is a more potent prognostic factor than its protein over-expression in human head-and-neck squamous-cell carcinoma. Int J Cancer. 1997 Dec 19;74(6):576–581. doi: 10.1002/(sici)1097-0215(19971219)74:6<576::aid-ijc3>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  25. Kyritsis A. P., Zhang B., Zhang W., Xiao M., Takeshima H., Bondy M. L., Cunningham J. E., Levin V. A., Bruner J. Mutations of the p16 gene in gliomas. Oncogene. 1996 Jan 4;12(1):63–67. [PubMed] [Google Scholar]
  26. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  27. Li Y., Graham C., Lacy S., Duncan A. M., Whyte P. The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev. 1993 Dec;7(12A):2366–2377. doi: 10.1101/gad.7.12a.2366. [DOI] [PubMed] [Google Scholar]
  28. Liu Q., Neuhausen S., McClure M., Frye C., Weaver-Feldhaus J., Gruis N. A., Eddington K., Allalunis-Turner M. J., Skolnick M. H., Fujimura F. K. CDKN2 (MTS1) tumor suppressor gene mutations in human tumor cell lines. Oncogene. 1995 Dec 7;11(11):2455–2455. [PubMed] [Google Scholar]
  29. Lukas J., Parry D., Aagaard L., Mann D. J., Bartkova J., Strauss M., Peters G., Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995 Jun 8;375(6531):503–506. doi: 10.1038/375503a0. [DOI] [PubMed] [Google Scholar]
  30. Martin K., Trouche D., Hagemeier C., Sørensen T. S., La Thangue N. B., Kouzarides T. Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature. 1995 Jun 22;375(6533):691–694. doi: 10.1038/375691a0. [DOI] [PubMed] [Google Scholar]
  31. Mayol X., Graña X., Baldi A., Sang N., Hu Q., Giordano A. Cloning of a new member of the retinoblastoma gene family (pRb2) which binds to the E1A transforming domain. Oncogene. 1993 Sep;8(9):2561–2566. [PubMed] [Google Scholar]
  32. Medema R. H., Herrera R. E., Lam F., Weinberg R. A. Growth suppression by p16ink4 requires functional retinoblastoma protein. Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6289–6293. doi: 10.1073/pnas.92.14.6289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mori T., Miura K., Aoki T., Nishihira T., Mori S., Nakamura Y. Frequent somatic mutation of the MTS1/CDK4I (multiple tumor suppressor/cyclin-dependent kinase 4 inhibitor) gene in esophageal squamous cell carcinoma. Cancer Res. 1994 Jul 1;54(13):3396–3397. [PubMed] [Google Scholar]
  34. Ohtsubo M., Roberts J. M. Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science. 1993 Mar 26;259(5103):1908–1912. doi: 10.1126/science.8384376. [DOI] [PubMed] [Google Scholar]
  35. Olshan A. F., Weissler M. C., Pei H., Conway K., Anderson S., Fried D. B., Yarbrough W. G. Alterations of the p16 gene in head and neck cancer: frequency and association with p53, PRAD-1 and HPV. Oncogene. 1997 Feb 20;14(7):811–818. doi: 10.1038/sj.onc.1200892. [DOI] [PubMed] [Google Scholar]
  36. Otterson G. A., Khleif S. N., Chen W., Coxon A. B., Kaye F. J. CDKN2 gene silencing in lung cancer by DNA hypermethylation and kinetics of p16INK4 protein induction by 5-aza 2'deoxycytidine. Oncogene. 1995 Sep 21;11(6):1211–1216. [PubMed] [Google Scholar]
  37. Papadimitrakopoulou V., Izzo J., Lippman S. M., Lee J. S., Fan Y. H., Clayman G., Ro J. Y., Hittelman W. N., Lotan R., Hong W. K. Frequent inactivation of p16INK4a in oral premalignant lesions. Oncogene. 1997 Apr 17;14(15):1799–1803. doi: 10.1038/sj.onc.1201010. [DOI] [PubMed] [Google Scholar]
  38. Parry D., Bates S., Mann D. J., Peters G. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J. 1995 Feb 1;14(3):503–511. doi: 10.1002/j.1460-2075.1995.tb07026.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Patel V., Jakus J., Harris C. M., Ensley J. F., Robbins K. C., Yeudall W. A. Altered expression and activity of G1/S cyclins and cyclin-dependent kinases characterize squamous cell carcinomas of the head and neck. Int J Cancer. 1997 Nov 14;73(4):551–555. doi: 10.1002/(sici)1097-0215(19971114)73:4<551::aid-ijc16>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  40. Pomerantz J., Schreiber-Agus N., Liégeois N. J., Silverman A., Alland L., Chin L., Potes J., Chen K., Orlow I., Lee H. W. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell. 1998 Mar 20;92(6):713–723. doi: 10.1016/s0092-8674(00)81400-2. [DOI] [PubMed] [Google Scholar]
  41. Quelle D. E., Cheng M., Ashmun R. A., Sherr C. J. Cancer-associated mutations at the INK4a locus cancel cell cycle arrest by p16INK4a but not by the alternative reading frame protein p19ARF. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):669–673. doi: 10.1073/pnas.94.2.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Quelle D. E., Zindy F., Ashmun R. A., Sherr C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995 Dec 15;83(6):993–1000. doi: 10.1016/0092-8674(95)90214-7. [DOI] [PubMed] [Google Scholar]
  43. Reed A. L., Califano J., Cairns P., Westra W. H., Jones R. M., Koch W., Ahrendt S., Eby Y., Sewell D., Nawroz H. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res. 1996 Aug 15;56(16):3630–3633. [PubMed] [Google Scholar]
  44. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  45. Serrano M., Lee H., Chin L., Cordon-Cardo C., Beach D., DePinho R. A. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996 Apr 5;85(1):27–37. doi: 10.1016/s0092-8674(00)81079-x. [DOI] [PubMed] [Google Scholar]
  46. Shapiro G. I., Park J. E., Edwards C. D., Mao L., Merlo A., Sidransky D., Ewen M. E., Rollins B. J. Multiple mechanisms of p16INK4A inactivation in non-small cell lung cancer cell lines. Cancer Res. 1995 Dec 15;55(24):6200–6209. [PubMed] [Google Scholar]
  47. Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
  48. Steingrimsdottir H., Penhallow J., Farzaneh F., Johnson N., Tavassoli M. Detection of p53 mutations in oral cancer samples using a sensitive PCR-based method. Biochem Soc Trans. 1997 Feb;25(1):315–318. doi: 10.1042/bst0250315. [DOI] [PubMed] [Google Scholar]
  49. Stone S., Jiang P., Dayananth P., Tavtigian S. V., Katcher H., Parry D., Peters G., Kamb A. Complex structure and regulation of the P16 (MTS1) locus. Cancer Res. 1995 Jul 15;55(14):2988–2994. [PubMed] [Google Scholar]
  50. Suzuki T., Kitao S., Matsushime H., Yoshida M. HTLV-1 Tax protein interacts with cyclin-dependent kinase inhibitor p16INK4A and counteracts its inhibitory activity towards CDK4. EMBO J. 1996 Apr 1;15(7):1607–1614. [PMC free article] [PubMed] [Google Scholar]
  51. Tam S. W., Shay J. W., Pagano M. Differential expression and cell cycle regulation of the cyclin-dependent kinase 4 inhibitor p16Ink4. Cancer Res. 1994 Nov 15;54(22):5816–5820. [PubMed] [Google Scholar]
  52. Timmermann S., Hinds P. W., Münger K. Elevated activity of cyclin-dependent kinase 6 in human squamous cell carcinoma lines. Cell Growth Differ. 1997 Apr;8(4):361–370. [PubMed] [Google Scholar]
  53. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. 1979. Biotechnology. 1992;24:145–149. [PubMed] [Google Scholar]
  54. Wang H. G., Draetta G., Moran E. E1A induces phosphorylation of the retinoblastoma protein independently of direct physical association between the E1A and retinoblastoma products. Mol Cell Biol. 1991 Aug;11(8):4253–4265. doi: 10.1128/mcb.11.8.4253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  56. Welcker M., Lukas J., Strauss M., Bartek J. Enhanced protein stability: a novel mechanism of D-type cyclin over-abundance identified in human sarcoma cells. Oncogene. 1996 Jul 18;13(2):419–425. [PubMed] [Google Scholar]
  57. Wong D. T., Todd R., Tsuji T., Donoff R. B. Molecular biology of human oral cancer. Crit Rev Oral Biol Med. 1996;7(4):319–328. doi: 10.1177/10454411960070040201. [DOI] [PubMed] [Google Scholar]
  58. Xiao Z. X., Chen J., Levine A. J., Modjtahedi N., Xing J., Sellers W. R., Livingston D. M. Interaction between the retinoblastoma protein and the oncoprotein MDM2. Nature. 1995 Jun 22;375(6533):694–698. doi: 10.1038/375694a0. [DOI] [PubMed] [Google Scholar]
  59. Xiong Y., Hannon G. J., Zhang H., Casso D., Kobayashi R., Beach D. p21 is a universal inhibitor of cyclin kinases. Nature. 1993 Dec 16;366(6456):701–704. doi: 10.1038/366701a0. [DOI] [PubMed] [Google Scholar]
  60. Yeudall W. A., Paterson I. C., Patel V., Prime S. S. Presence of human papillomavirus sequences in tumour-derived human oral keratinocytes expressing mutant p53. Eur J Cancer B Oral Oncol. 1995 Mar;31B(2):136–143. doi: 10.1016/0964-1955(94)00030-8. [DOI] [PubMed] [Google Scholar]
  61. Yoo G. H., Xu H. J., Brennan J. A., Westra W., Hruban R. H., Koch W., Benedict W. F., Sidransky D. Infrequent inactivation of the retinoblastoma gene despite frequent loss of chromosome 13q in head and neck squamous cell carcinoma. Cancer Res. 1994 Sep 1;54(17):4603–4606. [PubMed] [Google Scholar]
  62. Yoshida S., Todoroki T., Ichikawa Y., Hanai S., Suzuki H., Hori M., Fukao K., Miwa M., Uchida K. Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancers. Cancer Res. 1995 Jul 1;55(13):2756–2760. [PubMed] [Google Scholar]
  63. Zhang S. Y., Klein-Szanto A. J., Sauter E. R., Shafarenko M., Mitsunaga S., Nobori T., Carson D. A., Ridge J. A., Goodrow T. L. Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res. 1994 Oct 1;54(19):5050–5053. [PubMed] [Google Scholar]
  64. Zhang Y., Xiong Y., Yarbrough W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998 Mar 20;92(6):725–734. doi: 10.1016/s0092-8674(00)81401-4. [DOI] [PubMed] [Google Scholar]
  65. Zhou P., Jiang W., Weghorst C. M., Weinstein I. B. Overexpression of cyclin D1 enhances gene amplification. Cancer Res. 1996 Jan 1;56(1):36–39. [PubMed] [Google Scholar]
  66. Zhou X., Tarmin L., Yin J., Jiang H. Y., Suzuki H., Rhyu M. G., Abraham J. M., Meltzer S. J. The MTS1 gene is frequently mutated in primary human esophageal tumors. Oncogene. 1994 Dec;9(12):3737–3741. [PubMed] [Google Scholar]
  67. van der Riet P., Nawroz H., Hruban R. H., Corio R., Tokino K., Koch W., Sidransky D. Frequent loss of chromosome 9p21-22 early in head and neck cancer progression. Cancer Res. 1994 Mar 1;54(5):1156–1158. [PubMed] [Google Scholar]

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