Correspondence

TP53 Mutations in Head and Neck Cancer

N Engl J Med 2008; 358:1194-1195March 13, 2008

Article

To the Editor:

Poeta et al. (Dec. 20 issue)1 report that a disruptive alteration of the gene for the tumor-suppressor protein p53 (TP53), as compared with the absence of a TP53 mutation, had an independent, significant association with decreased survival in patients with squamous-cell carcinoma of the head and neck. TP53 mutations were screened with the use of the GeneChip p53 assay (Affymetrix). However, frameshift mutations (from insertions or deletions in the p53 gene) cannot be detected with the GeneChip method.2,3 This important limitation biases the study by Poeta and colleagues because such frameshift mutations represent up to 20% of all known p53 mutations in head and neck cancer.4

Dirk Beutner, M.D.
Jens-Peter Klussmann, M.D.
University of Cologne, 50924 Cologne, Germany
dirk.beutner@uni-koeln.de

Orlando Guntinas-Lichius, M.D.
University of Jena, 07743 Jena, Germany

4 References

1
Poeta ML, Manola J, Goldwasser MA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 2007;357:2552-2561
Full Text | Web of Science | Medline

2
Ahrendt SA, Halachmi S, Chow JT, et al. Rapid p53 sequence analysis in primary lung cancer using an oligonucleotide probe array. Proc Natl Acad Sci U S A 1999;96:7382-7387
CrossRef | Web of Science | Medline

3
Wikman FP, Lu ML, Thykjaer T, et al. Evaluation of the performance of a p53 sequencing microarray chip using 140 previously sequenced bladder tumor samples. Clin Chem 2000;46:1555-1561
Web of Science | Medline

4
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
Web of Science | Medline

To the Editor:

Poeta et al. conclude that disruptive TP53 mutations are associated with reduced survival among patients with squamous-cell carcinoma of the head and neck. The authors remark that conclusions with regard to oropharyngeal subsites may not be appropriate, since the presence of the human papillomavirus (HPV), which interacts with TP53, was not determined.

We have characterized 90 oropharyngeal squamous-cell carcinomas for HPV and TP53 status.1 Independently of the functional properties of the TP53 mutations, HPV-positive patients had better survival than HPV-negative patients. Among HPV-negative patients, there was no difference in survival between those with mutated TP53 and those with wild-type TP53. Unlike Poeta et al., we did not analyze the entire TP53 coding region, only exons 5 through 8 and exon 42 in all and most cases, respectively. Moreover, in cases in which there was p53 immunoreactivity of more than 50%, we performed additional sequencing for exons 9 and 10. With the classification of TP53 status as wild type, disruptive, or nondisruptive in our entire series, no significant prognostic difference was found, nor was there a difference in a separate analysis of HPV-negative patients. This suggests that oropharyngeal squamous-cell carcinoma has biologic prognostic variables that differ from those for other squamous-cell carcinomas of the head and neck.

Federica Perrone, Ph.D.
Paolo Bossi, M.D.
Lisa Licitra, M.D.
Istituto Nazionale Tumori, 20133 Milan, Italy
federica.perrone@istitutotumori.mi.it

2 References

1
Licitra L, Perrone F, Bossi P, et al. High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 2006;24:5630-5636
CrossRef | Web of Science | Medline

2
Perrone F, Mariani L, Pastore E, et al. p53 Codon 72 polymorphisms in human papillomavirus-negative and human papillomavirus-positive squamous cell carcinomas of the oropharynx. Cancer 2007;109:2461-2465
CrossRef | Web of Science | Medline

Author/Editor Response

In response to Beutner and colleagues, it is true that the Affymetrix p53 gene chip does not identify all mutations, but the later version of the chip, which we used, does identify single-base deletions and insertions that would account for many of the possible frameshift mutations. In fact, 12 frameshift mutations were included in our cohort (in 12 of 224 patients [5.4%]), 10 of which we scored as “disruptive” in that they resulted in a “stop” sequence later within the gene. The proportion of frameshift mutations that we found in this cohort closely resembles that in our earlier study of 129 head and neck cancers analyzed by direct sequencing of TP53, 1 in which 7% of all mutations were frameshifts. The International Agency for Reseach on Cancer currently reports that 17.2% of TP53 mutations in head and neck cancer are deletions and insertions.2

The 10 patients with disruptive frameshift mutations in our current cohort had a median survival of 2.2 years — nearly identical to the median survival of 2.0 years for the 75 patients with other disruptive mutations (P=0.95). It is logical to extrapolate that the majority of any frameshift mutations we may have missed would also be disruptive, and their identification would therefore serve to reassign some patients with poor outcomes from the wild-type group to the disruptive-mutation group, further enhancing the distinction in outcome based on mutation status that we were able to identify.

We agree with Perrone and colleagues that the evidence indicates a distinctive genetic pathway for tumorigenesis in the setting of HPV-related oropharyngeal tumors. The number of cases in their series and ours is insufficient to comment with statistical confidence regarding the prognostic effect of a TP53 mutation when it is present with HPV DNA, as compared with either alteration in isolation. Since as many as 70% of tonsil or tongue-base cancers have HPV, and HPV inactivates wild-type p53, a TP53 mutation would be expected to play a relatively minor role in this subgroup of squamous-cell carcinomas of the head and neck.

Wayne Koch, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 21287
wkoch@jhmi.edu

M. Luana Poeta, M.D.
University Campus Bio-Medico School of Medicine, 00155 Rome, Italy

Judith Manola, M.S.
Dana–Farber Cancer Institute, Boston, MA 02115

2 References

1
Brennan JA, Boyle JO, Koch WM, et al. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med 1995;332:712-717
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