TP53 Mutations in Head and Neck Cancer

The authors reply: 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 ex1. 2. trapolate 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.