PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma

Abstract

BackgroundRecent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway.Methods and resultsPIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]).ConclusionsOverall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma.

Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma

“…PIK3CA was the most frequently altered oncogene in our cohort (13% amplified or mutated) and was enriched in HPV-positive oropharynx cancers, consistent with prior reports (6,8,9,(13)(14)(15)(16). For the first time, we found that PIK3CA amplification was associated with significantly decreased PFS, whereas PIK3CA mutation was not associated with survival outcomes.…”

“…For the first time, we found that PIK3CA amplification was associated with significantly decreased PFS, whereas PIK3CA mutation was not associated with survival outcomes. Prior smaller studies were unable to identify a significant correlation between PI3K pathway activation and survival outcomes (9,15,17) and did not distinguish the relative contribution of various mechanisms of activation of the PI3K pathway (e.g., PIK3CA mutation vs. amplification vs. PTEN loss; 15). One study identified that PIK3CA amplification in 32% of 115 surgical HNSCC cases was associated with earlier relapse in a subset of patients without lymph node metastases (n ¼ 59, P ¼ 0.026; 17).…”

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

“…An unadjusted P value cut-off of 0.05 with fold change cut-off of C10 was used to generate this HPV classifier gene list. identified in SCCHN and have started to better identify the genetic landscape of SCCHN [45,52]. Some of these mutations appear to be more commonly observed in HPVpositive OPSCC [53].…”

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…Mutations and copy number alterations of PI3K pathway components, including PIK3CA amplifications and PTEN inactivation by loss or inactivation of gene copy, are particularly prevalent in HPV-positive tumors [36]. Indeed, in a study of patients with HPV-positive oropharyngeal cancer, PIK3CA mutations were observed in 31% of cases, with 20% of cases harboring PI3KCA amplifications and 33% of cases showing PTEN loss [37]. A separate study investigating genetic aberrations of SCCHN tumors also showed differences depending on HPV status.…”