Abstract Objective: To determine the relationship of p53 mutations in advanced laryngeal carcinomas to p53 immunohistochemistry, organ preservation, and patient survival. Design: Paraffin-embedded tumor specimens were obtained from patients enrolled in the Department of Veterans Affairs Laryngeal Cancer Cooperative Study, a multi-institutional randomized clinical trial comparing induction chemotherapy (cisplatin and fluorouracil) plus radiation therapy with surgery plus postoperative radiation therapy. Tumor specimens were analyzed for p53 mutations in exons 5 through 8 by using single-strand conformational polymorphism (SSCP) analysis followed by DNA sequencing of all variants. Fiveyear follow-up data were available for all patients studied. Subjects: Forty-four patients enrolled in the Department of Veterans Affairs Laryngeal Cancer Cooperative Study from whom paraffin-embedded tumor specimens were readily available. Results: p53 immunostaining did not correlate with p53 SSCP and DNA sequencing results. More than half (62% [16/26]) of the tumors that overexpressed p53 immunohistochemically did not have a detectable p53 gene mutation. Similarly, 39% (7/18) of tumors that did not overexpress p53 did have a p53 gene mutation. p53 mutations were present in 39% of tumors tested. Mutations within exon 5 made up 41% of p53 gene mutations in laryngeal carcinomas. Transitions were the most common type of mutation in this study (92% of mutations). Conclusions: The presence of a p53 mutation as detected by SSCP is associated with decreased patient survival. Further study is required to confirm this relationship and to determine whether specific p53 mutations predict organ preservation.Arch Otolaryngol Head Neck Surg. 1997;123:605-609 References 1. Jacobs C, Goffinet DR, Goffinets L, Kohler M, Fee WE. Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer: a report from the Northern California Oncology Group . Cancer . 1987; 60:1178-1183.Crossref 2. Karp D, Carter R, Vaughn C, et al. Voice preservation using induction chemotherapy plus radiation therapy as an alternative to laryngectomy in advanced head and neck cancer: long term follow-up . Proc Am Soc Clin Oncol. 1988; 7:152. 3. Wolf GT, Hong WK, Fisher S, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer . N Engl J Med. 1991;324:1685-1690.Crossref 4. Toohill RJ, Duncavage JA, Grossman TW, et al. The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies . Laryngoscope . 1987;97:407-412.Crossref 5. Yonish-Rouach E, Resnitzky D, Lotem J, Sachs L, Kimchi A, Oren M. Wildtype p53 induces apoptosis of myeloid leukemia cells that is inhibited by interleukin-6 . Nature . 1991;352:345-347.Crossref 6. Lotem J, Sachs L. Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents . Blood . 1991;82: 1092-1096. 7. Haldar S, Negrini M, Monne M, Sabbioni S, Croce CM. Down-regulation of bcl-2 by p53 in breast cancer cells . Cancer Res. 1994;54:2095-2097. 8. Bradford CR, Zhu S, Wolf GT, et al. Overexpression of p53 predicts organ preservation using induction chemotherapy and radiation in patients with advanced laryngeal cancer . Otolaryngol Head Neck Surg. 1995;113:408-412.Crossref 9. Sanbrook J, Fritsch EF, Maniatis T. Molecular Cloning. New York , NY: Cold Spring Harbor Laboratory; 1989:2. 10. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers . Science . 1991;253:49-53.Crossref 11. Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis . Cancer Res. 1994;54:4855-4878. 12. Fujita M, lnoue M, Tanizawa O, lwamoto S, Enomoto T. Alterations of the p53 gene in human primary cervical carcinoma with and without human papillomavirus infection . Cancer Res. 1992;52:5323-5328. 13. Xu L, Chen YT, Huvos AG, et al. Overexpression of p53 protein in squamous cell carcinomas of head and neck without apparent gene mutations . Diagn Mol Pathol. 1994;3:83-92.Crossref 14. Arai N, Nomura D, Yokota K, et al. Immunologically distinct p53 molecules generated by alternative splicing . Mol Cell Biol. 1986;6:3232-3239. 15. Koch WM, Brennan JA, Zahurak M, et al. p53 mutation is associated with locoregional recurrence but not decreased survival in head and neck squamous cell carcinoma. J Nati Cancer Inst. In press.
Archives of Otolaryngology - Head & Neck Surgery – American Medical Association
Published: Jun 1, 1997