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Clin Cancer Res. 2012 Jul 1;18(13):3705-13. doi: 10.1158/1078-0432.CCR-11-3271. Epub 2012 May 10.

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.

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  • 1Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

©2012 AACR.

PMID:
22577058
[PubMed - indexed for MEDLINE]
PMCID:
PMC3404728
Free PMC Article

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