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Original Article |

High Frequency of Activating PIK3CA Mutations in Human Papillomavirus–Positive Oropharyngeal Cancer

Anthony C. Nichols, MD; David A. Palma, MD, PhD; Winsion Chow, MD; Susan Tan, MD; Chandheeb Rajakumar, MD; Giananthony Rizzo, BSc; Kevin Fung, MD; Keith Kwan, MD; Brett Wehrli, MD; Eric Winquist, MD, MSc; James Koropatnick, PhD; Joe S. Mymryk, PhD; John Yoo, MD; John W. Barrett, PhD
JAMA Otolaryngol Head Neck Surg. 2013;139(6):617-622. doi:10.1001/jamaoto.2013.3210.
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Importance Large-scale whole-exome sequencing studies of head and neck squamous cell carcinoma (HNSCC) have established that the disease is dominated by frequent mutations in tumor suppressor genes with rare activating mutations in oncogenes that would be easily targetable with molecular agents. There was evidence in these reports, however, that activating mutations in phosphoinositide 3-kinase catalytic subunit p110α (PIK3CA) were common in patients with human papillomavirus (HPV)-positive tumors. We set out to test this prediction in oropharyngeal patient samples from our institution.

Objective To confirm whether activating mutations in PIK3CA are frequent in HPV-positive HNSCC because this mutated oncogene represents a potential therapeutic target.

Design, Setting, and Participants A retrospective search of the London Health Sciences Centre pathology database was performed to identify oropharyngeal cancer samples. DNA from pretreatment primary site biopsy samples from 87 patients were tested for high-risk HPV types 16 and 18 by real-time polymerase chain reaction.

Main Outcomes and Measures Samples were tested for activating mutations at the 3 mutational hot spots (codons 542, 545, and 1047) by polymerase chain reaction followed by Sanger sequencing using forward and reverse primers.

Results Only 4 of 41 HPV-negative tumors (10%) demonstrated PIK3CA hot spot mutations, including 3 at codon 1047 and 1 at codon 542. Of 46 HPV-positive tumors, 13 (28%) demonstrated activating PIK3CA mutations, including 7 at codon 542, 5 at codon 545, and 1 at codon 1047. The difference in PIK3CA mutation frequency was significantly different between HPV-positive and HPV-negative cancers (P = .03).

Conclusions and Relevance Although there has been a suggestion that activating PIK3CA mutations are common in HPV-positive HNSCC, to our knowledge, this is the first study to clearly identify this phenomenon. Targeting PIK3CA with molecular agents in HPV-positive patients may be a mechanism to improve cure rates and decrease treatment toxic effects in this rapidly growing cohort of patients.

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Figure. Examples of activating mutations at codons 542 (A), 545 (B), and 1047 (C). E indicates glutamic acid; I, isoleucine; K, lysine; H, histidine; R, arginine; T, threonine. The green boxed A indicates adenine; the blue boxed C, cytosine; the black boxed G, guanine; and the red boxed T, thymine.

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