title: PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy.
abstract: Non-small cell lung cancer (NSCLC) is still the leading cause of cancer-related deaths. The effect of the PI3K/PTEN/AKT/mTOR signaling pathway on cancer treatment, including NSCLC, has been well documented. In this study, we analyzed associations between genetic variations within this pathway and clinical outcomes following platinum-based chemotherapy in 168 patients with stage IIIB (wet) or stage IV NSCLC. Sixteen tagging SNPs in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) of this pathway and identified SNPs associated with development of toxicity and disease progression. We observed significantly increased toxicity for patients with PIK3CA:rs2699887 (OR: 3.86, 95% CI: 1.08-13.82). In contrast, a SNP in PTEN was associated with significantly reduced risk for chemotherapeutic toxicity (OR: 0.44, 95% CI: 0.20-0.95). We identified three SNPs in AKT1 resulting in significantly decreased risks of distant progression in patients carrying at least one variant allele with HRs of 0.66 (95% CI: 0.45-0.97), 0.52 (95% CI: 0.35-0.77), and 0.62 (95% CI: 0.42-0.91) for rs3803304, rs2498804, and rs1130214, respectively. Furthermore, these same variants conferred nearly 2-fold increased progression-free survival times. The current study provides evidence that genetic variations within the PI3K/PTEN/AKT/mTOR signaling pathway are associated with variation in clinical outcomes of NSCLC patients. With further validation, our findings may provide additional biomarkers for customized treatment of platinum-based chemotherapy for NSCLC.
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Pu
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: David J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D058534:Class I Phosphatidylinositol 3-Kinases; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016190:Carboplatin; D002945:Cisplatin; D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; C494921:AKT2 protein, human; C494929:PTEN protein, human
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