TY - JOUR
T1 - Pharmacogenetic and germline prognostic markers of lung cancer
AU - Horgan, Anne M.
AU - Yang, Boming
AU - Azad, Abul Kalam
AU - Amir, Eitan
AU - John, Thomas
AU - Cescon, David W.
AU - Wheatley-Price, Paul
AU - Hung, Rayjean J.
AU - Shepherd, Frances A.
AU - Liu, Geoffrey
N1 - Funding Information:
Supported by Alan B. Brown Chair in Molecular Genomics; Ontario Institute for Cancer Research Operating Grants; Posluns Family Foundation; Cancer Care Ontario Chair in Experimental Therapeutics and Population Studies; and Division of Hematology/Oncology, Princess Margaret Hospital/University Health Network, University of Toronto, Ontario, Canada (to A.H.).
PY - 2011/2
Y1 - 2011/2
N2 - Lung cancer is the leading global cause of cancer-related mortality. Interindividual variability in treatment response and cancer outcomes has focused attention on genetic polymorphisms as prognostic markers. We evaluated the overall contribution of candidate polymorphism association studies to our current understanding of the genetic predictors of lung cancer outcomes. Methods: We examined the results of 90 studies that evaluated associations between genetic polymorphisms and lung cancer outcomes published between January 1990 and May 2009. Results: A total of 170 genetic variations in 90 studies were identified. Overall survival was a primary outcome in 81% of the studies and toxicity in 19%. Candidate polymorphisms in the DNA repair/synthesis pathway were the most frequently studied. Strong evidence in large-scale confirmatory studies of any single polymorphism was lacking. Polymorphisms of EGFR, XRCC1, and ERCC1 were associated with pharmacogenetic outcomes, whereas polymorphisms of MDM2, p53, and GSTM1 were associated with prognostic outcomes. All remaining polymorphisms had results lacking or failing replication testing. Heterogeneity in study populations, incomplete reporting of important population or study characteristics, inadequate power, and inconsistencies in methodology were common. Conclusions: Although the quality of existing studies involving the candidate polymorphism approach is highly variable, a small set of candidate polymorphisms was identified as potential biomarkers of clinical or pharmacogenetic outcome and would benefit from further replication testing. Newer approaches including haplotype tagging, pathway, genome-wide association, and combination methods with validative approaches may facilitate a more accurate prediction of lung cancer outcomes by genetic variation.
AB - Lung cancer is the leading global cause of cancer-related mortality. Interindividual variability in treatment response and cancer outcomes has focused attention on genetic polymorphisms as prognostic markers. We evaluated the overall contribution of candidate polymorphism association studies to our current understanding of the genetic predictors of lung cancer outcomes. Methods: We examined the results of 90 studies that evaluated associations between genetic polymorphisms and lung cancer outcomes published between January 1990 and May 2009. Results: A total of 170 genetic variations in 90 studies were identified. Overall survival was a primary outcome in 81% of the studies and toxicity in 19%. Candidate polymorphisms in the DNA repair/synthesis pathway were the most frequently studied. Strong evidence in large-scale confirmatory studies of any single polymorphism was lacking. Polymorphisms of EGFR, XRCC1, and ERCC1 were associated with pharmacogenetic outcomes, whereas polymorphisms of MDM2, p53, and GSTM1 were associated with prognostic outcomes. All remaining polymorphisms had results lacking or failing replication testing. Heterogeneity in study populations, incomplete reporting of important population or study characteristics, inadequate power, and inconsistencies in methodology were common. Conclusions: Although the quality of existing studies involving the candidate polymorphism approach is highly variable, a small set of candidate polymorphisms was identified as potential biomarkers of clinical or pharmacogenetic outcome and would benefit from further replication testing. Newer approaches including haplotype tagging, pathway, genome-wide association, and combination methods with validative approaches may facilitate a more accurate prediction of lung cancer outcomes by genetic variation.
KW - Lung cancer
KW - Outcomes
KW - Prognosis
KW - Single-nucleotide polymorphisms
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U2 - 10.1097/JTO.0b013e3181ffe909
DO - 10.1097/JTO.0b013e3181ffe909
M3 - Article
AN - SCOPUS:79551513215
SN - 1556-0864
VL - 6
SP - 296
EP - 304
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 2
ER -