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Lung Cancer New Molecular Targets in Lung Adenocarcinoma Fergal C Kelleher, MSc, MRCSI, MRCP, 1 Andrew J Colebatch, BSc (Med), MBBS 2,3 and Aparna Rao, MBBS, MClinTRes, FRACP 4 1. Lecturer in Medical Oncology, St Vincent’s University Hospital and University College Dublin, Dublin, Ireland; 2. Registrar in Anatomical Pathology, Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; 3. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia; 4. PhD Candidate and Medical Oncologist, Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Abstract Lung cancer is designated as either non-small-cell lung cancer (NSCLC) or small-cell lung cancer. There are three subtypes of NSCLC: adenocarcinoma (48 %), squamous cell carcinoma (28 %), and large-cell carcinoma (24 %). Epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and ROS1 rearrangements are co-associated with lung adenocarcinoma in never-smokers. Histologically, lung adenocarcinoma is sub-divided into papillary, acinar, bronchioalveolar, and solid subtypes. A superseding molecular sub- classification is emerging with important therapeutic implications. Secondary resistance to medications targeting these molecular abnormalities does invariably occur. It is anticipated that strategies including drugs with increased receptor binding affinity, altered medication pharmacodynamic profiles, and combinatorial approaches will emerge. Keywords Adenocarcinoma, tyrosine kinase, crizotinib, sequencing, clinical correlates Disclosure: The authors have no conflicts of interest to declare. Received: August 9, 2013 Accepted: October 5, 2013 Citation: Oncology & Hematology Review (US), 2013;9(2):122–8 Correspondence: Fergal C Kelleher, MSc, MRCSI, MRCP, Department of Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland. E: fergalkelleher@hotmail.com Annually, 1.3 million cases of NSCLC occur. 1 Despite smoking being the most important environmental causative factor for lung cancer, 10  % of lung cancers occur in never-smokers, thus emphasizing the importance of genetic factors. 2 Detection methods for genomic alterations include array-based profiling, targeted sequencing, and whole-genome sequencing. The following driver genetic alterations and respective frequencies occur in lung adenocarcinoma: EGFR (5–15 %), ALK (5–15 %), and KRAS (>15 %). Genes with a mutation rate <5  % include BRAF, PIK3CA, MAP2K1, MET, and HER2. The ability to detect such driver mutations in a majority of lung cancer patient specimens has been demonstrated in large genomic projects, such as the Lung Cancer Mutation Consortium (LCMC), 3 which seeks to not only determine driver mutations but also allow clinicians to use this knowledge to use appropriate targeted therapies or enroll patients into relevant clinical trials. In 2012, next generation sequencing of 183 lung adenocarcinomas was reported. 4 New findings that supplemented existing literature included recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations in ARID1A and RBM10. Loss of function mutations and deletions in tumor suppressor genes are not easy to therapeutically target but deserve inclusion. These include LKB1, TP53, RB1, NF1, CDKN2A, SMARCA4, and KEAP1. 5 Inactivation of p16Ink4 also occurs in lung adenocarcinoma and is associated with cigarette smoking. Finally, somatic focal amplifications of NKX2-1 as well as recurrent in- frame fusions of KIF5B and RET can also occur. Molecular Biology In an assessment of 188 cases of lung adenocarcinoma in 2008, DNA sequencing was performed on 623 selected genes. Twenty-six genes 122 emerged that were frequently mutated and considered likely involved in carcinogenesis. 5 The inferred significantly mutated pathways were the MAPK, Wnt, p53 signaling, cell cycle, and mammalian target of rapamycin (mTOR) pathways. Clinically, KRAS mutations and LKB1 mutations were correlated with smoking status. EGFR mutations were correlated with never-smoker status. 6 Pathologically, mutations of LRP1B, TP53, and INHBA were negatively correlated with acinar, papillary, and bronchioalveolar subtypes, but were significantly positively correlated with the solid subtype. By contrast, EGFR mutations were negatively correlated with the solid subtype and positively correlated with the papillary subtype. Molecular alterations of importance in lung adenocarcinoma are also not solely restricted to mutations, but include amplifications or gene rearrangements. Ethnic differences exist in different studied populations with differing molecular tumor characteristics and reported frequencies. The clinician must use interpretive caution when applying data between different groups—Asian and Western populations differences are a notable example. The incidence in lung adenocarcinoma of commonly mutated genes and rearrangements in ethnically different populations is detailed in Figure 1. A study comprising an ethnically heterogeneous series of non- small-cell lung cancer (NSCLC) found LKB1 mutations in 17 % of NSCLC of US origin compared with 5 % of Korean cases (p=0.001). 6 EGFR mutations are more frequent in NSCLC arising in patients of Asian ethnicity. Patterns of co-occurrence and mutual exclusivity of genomic alterations are also important. In another case series of NSCLC (n=1,683) ALK rearrangements were mutually exclusive of EGFR or KRAS mutations. 7 © Tou c h M E d ica l ME d ia 2013