Human Genetic Variation: A Foundation for Rational Diagnosis and Individualized Treatment of Lung Cancer

O.   M.   Shaw; N.   L.   Misso; B.   P.   Shelton; K.   D.   Bhoola

doi:10.2174/187569209788653989

Abstract

Lung cancer is the fourth most frequently diagnosed human malignancy and the most common cause of cancerrelated deaths in the western world. Consideration of human genetic variation in the post-genomics era increased the rate of discovery of novel therapeutic targets that could become the mainstay of personalized anti-cancer treatment. These targets include tumour suppressor genes such as tumour protein (TP)53, as well as oncogenes and cell cycle genes, such as epidermal growth factor receptor (EGFR), MYC, protein kinase and cyclin-dependent kinase inhibitor (CDKN2A) genes. Polymorphisms in the cytochrome P450, excision repair cross-complementing (ERCC) and nicotinic acetylcholine receptor (CHRNA) genes strongly influence the risk of developing lung cancer, and the risk attributable to these polymorphisms differs in non-smokers compared to smokers. Variants in the EGFR gene occur more frequently among women and non-smokers with lung adenocarcinoma, and are strongly associated with sensitivity to the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. Polymorphisms in the ERCC1, ATP-binding cassette, uridine diphosphate glucuronosyltransferase, cytidine deaminase and ribonucleotide reductase subunit M1 genes influence the metabolism, clinical efficacy and/or toxicity of other drugs used to treat lung cancer, including cisplatin, paclitaxel, irinotecan and gemcitabine. This review presents a critical synthesis of the major genetic changes associated with lung carcinogenesis, as well as the significance of pharmacogenetics approaches to forecast therapeutic response in lung cancer. We underscore that mechanism-based associations of human genetic variation with pharmacodynamics of current and emerging medicines will provide additional decision tools for anti-cancer pharmacotherapy to be personalized in clinical care of patients with lung cancer.

Keywords: Lung cancer, disease susceptibility markers, drug targets, individualized therapy, theragnostics