title: Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention.
abstract: OBJECTIVE
  The development of second primary tumors (SPT) or recurrence alters prognosis for curatively treated head and neck squamous cell carcinoma (HNSCC) patients. The 13-cis-Retinoic acid (13-cRA) has been tested as a chemoprevention agent in clinical trials with mixed results. Therefore, we investigated whether genetic variants in the PI3K/PTEN/AKT/mTOR pathway could serve as biomarkers to identify which patients are at high risk of an SPT/recurrence, while also predicting response to 13-cRA chemoprevention.
  
  
  METHODS
  A total of 137 pathway single-nucleotide polymorphisms were genotyped in 440 patients from the Retinoid Head and Neck Second Primary Trial and assessed for SPT/recurrence risk and response to 13-cRA. Risk models were created based on epidemiology, clinical, and genetic data.
  
  
  RESULTS
  Twenty-two genetic loci were associated with increased SPT/recurrence risk, with six also being associated with a significant benefit following chemoprevention. Combined analysis of these high-risk/high-benefit loci identified a significant (P = 1.54 × 10(-4)) dose-response relationship for SPT/recurrence risk, with patients carrying four to five high-risk genotypes having a 3.76-fold [95% Confidence Interval (CI), 1.87-7.57] increase in risk in the placebo group (n = 215). Patients carrying four to five high-risk loci showed the most benefit from 13-cRA chemoprevention, with a 73% reduction in SPT/recurrence (95% CI, 0.13-0.58) compared with those with the same number of high-risk genotypes who were randomized to receive placebo. Incorporation of these loci into a risk model significantly improved the discriminatory ability over models with epidemiology, clinical, and previously identified genetic variables.
  
  
  CONCLUSIONS
  These results show that loci within this important pathway could identify individuals with a high-risk/high-benefit profile and are a step toward personalized chemoprevention for HNSCC patients.
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Etzel
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Reuben
authors.initials: R
authors.lastname: Lotan
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D015474:Isotretinoin / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000517:prevention & control; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000517:prevention & control; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012372:ROC Curve; D016032:Randomized Controlled Trials as Topic; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D055504:Insulin Receptor Substrate Proteins; D015474:Isotretinoin; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D025521:Tumor Suppressor Proteins; C494929:PTEN protein, human