Genomic alterations in lung adenocarcinoma.

Treatment for non-small-cell lung cancer is evolving from the use of cytotoxic chemotherapy to personalised treatment based on molecular alterations. This past decade has witnessed substantial progress in the treatment of patients with EGFR mutations and ALK rearrangements, and it is now possible to study complex genomic alterations in cancer using next-generation sequencing. Sequencing data from large-scale consortia, such as The Cancer Genome Atlas, as well as several independent groups, have helped identify novel drivers and potentially targetable alterations in lung adenocarcinomas. These data clearly suggest that lung adenocarcinoma is associated with distinct genomic alterations compared with other lung cancer subtypes, and highlight the widespread molecular heterogeneity that underlies the disease. In this Review, we discuss some of the key findings from genomic studies of lung adenocarcinoma.

[1]  A. Santoro,et al.  Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  P. Schultz,et al.  A small-molecule inducer of the antioxidant response element. , 2010, Chemistry & biology.

[3]  K. Cibulskis,et al.  Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer , 2012, Nature Genetics.

[4]  Weimin Chen,et al.  Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. , 2008, Carcinogenesis.

[5]  M Broggini,et al.  Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer genes , 2014 .

[7]  C. Wolf,et al.  Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha , 2007, Proceedings of the National Academy of Sciences.

[8]  P. Jänne,et al.  AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. , 2015, The New England journal of medicine.

[9]  Angela N. Brooks,et al.  Mapping the Hallmarks of Lung Adenocarcinoma with Massively Parallel Sequencing , 2012, Cell.

[10]  Matthew D. Wilkerson,et al.  Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation , 2012, PloS one.

[11]  Yoo Jin Jung,et al.  The transcriptional landscape and mutational profile of lung adenocarcinoma , 2012, Genome research.

[12]  Krister Wennerberg,et al.  The Ras superfamily at a glance , 2005, Journal of Cell Science.

[13]  J Wala,et al.  Oncogenic RIT1 mutations in lung adenocarcinoma , 2014, Oncogene.

[14]  M. Meyerson,et al.  BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models , 2008, Oncogene.

[15]  Travis J Cohoon,et al.  Efficacy of BET Bromodomain Inhibition in Kras-Mutant Non–Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[16]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[17]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[18]  E. Birney,et al.  A small cell lung cancer genome reports complex tobacco exposure signatures , 2009, Nature.

[19]  S. Gabriel,et al.  Discovery and saturation analysis of cancer genes across 21 tumor types , 2014, Nature.

[20]  W. Travis,et al.  Pathology of lung cancer. , 2011, Clinics in chest medicine.

[21]  N. Girard,et al.  New driver mutations in non-small-cell lung cancer. , 2011, The Lancet. Oncology.

[22]  P. Minoo,et al.  Inhibition of distal lung morphogenesis in Nkx2.1(−/−) embryos , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[23]  S. Miyano,et al.  Novel recurrent mutations in the RAS-like GTP-binding gene RIT1 in myeloid malignancies , 2013, Leukemia.

[24]  B. Spencer‐Dene,et al.  Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance , 2013, Cancer cell.

[25]  M. Ladanyi,et al.  Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase Mutations in Lung Adenocarcinomas , 2012, Clinical Cancer Research.

[26]  Yu Cao,et al.  Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing , 2014, Science.

[27]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[28]  M. Meyerson,et al.  Non-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272. , 2006, Cancer research.

[29]  Heidi Ledford Big science: The cancer genome challenge , 2010, Nature.

[30]  A. Gemma,et al.  F1000 highlights , 2010 .

[31]  Peter J. Campbell,et al.  Evolution of the cancer genome , 2012, Nature Reviews Genetics.

[32]  L. Penn,et al.  Reflecting on 25 years with MYC , 2008, Nature Reviews Cancer.

[33]  P. Hurlin,et al.  The MAX-interacting transcription factor network. , 2006, Seminars in cancer biology.

[34]  V. Tergaonkar,et al.  Noncanonical functions of telomerase: implications in telomerase-targeted cancer therapies. , 2014, Cancer research.

[35]  Jian Zhang,et al.  Misregulation of pre-mRNA alternative splicing in cancer. , 2013, Cancer discovery.

[36]  Michael Thomas,et al.  Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. , 2013, The New England journal of medicine.

[37]  S. Gabriel,et al.  Pan-cancer patterns of somatic copy-number alteration , 2013, Nature Genetics.

[38]  G. Lopes,et al.  Impact of biomarkers on clinical trial risk in breast cancer , 2012, Breast Cancer Research and Treatment.

[39]  Robert Gentleman,et al.  Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer , 2012, Nature Genetics.

[40]  C. Rudin,et al.  Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. , 2013 .

[41]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[42]  William Pao,et al.  Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  M. Dawson,et al.  Cancer Epigenetics: From Mechanism to Therapy , 2012, Cell.

[44]  Jeffrey W. Clark,et al.  Crizotinib in ROS1-rearranged non-small-cell lung cancer. , 2014, The New England journal of medicine.

[45]  A. Iafrate,et al.  Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC). , 2014 .

[46]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[47]  A. Regev,et al.  SOX2 Is an Amplified Lineage Survival Oncogene in Lung and Esophageal Squamous Cell Carcinomas , 2009, Nature Genetics.

[48]  Stefano Monti,et al.  Gene expression profiling reveals reproducible human lung adenocarcinoma subtypes in multiple independent patient cohorts. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  I. Umelo,et al.  Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. , 2012, Lung cancer.

[50]  Antonio Marchetti,et al.  Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.

[52]  Andrew D. Yates,et al.  Athletics: Momentous sprint at the 2156 Olympics? , 2004, Nature.

[53]  Mariano Provencio,et al.  Screening for epidermal growth factor receptor mutations in lung cancer. , 2009, The New England journal of medicine.

[54]  W. Wilson,et al.  Precision Treatment of Distinct Molecular Subtypes of Diffuse Large B-cell Lymphoma: Ascribing Treatment Based on the Molecular Phenotype , 2014, Clinical Cancer Research.

[55]  S. Kobayashi,et al.  EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. , 2012, The Lancet. Oncology.

[56]  Michael Peyton,et al.  Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer , 2013, Cell.

[57]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[58]  Rakesh Nagarajan,et al.  Clinical next‐generation sequencing in patients with non–small cell lung cancer , 2015, Cancer.

[59]  Benjamin E. Gross,et al.  Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal , 2013, Science Signaling.

[60]  Thomas D. Wu,et al.  Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events , 2012, Genome research.

[61]  B. Hogan,et al.  Preparing for the first breath: genetic and cellular mechanisms in lung development. , 2010, Developmental cell.

[62]  Donna D. Zhang,et al.  Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism , 2011, Proceedings of the National Academy of Sciences.

[63]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[64]  Kevan M. Shokat,et al.  K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions , 2013, Nature.

[65]  J. Engelman,et al.  Ceritinib in ALK-rearranged non-small-cell lung cancer. , 2014, The New England journal of medicine.

[66]  A. Shaw,et al.  Novel targets in non-small cell lung cancer: ROS1 and RET fusions. , 2013, The oncologist.

[67]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[68]  L. Garraway,et al.  Oncogenic and drug sensitive NTRK1 rearrangements in lung cancer , 2013, Nature Medicine.

[69]  J. Neal,et al.  Rociletinib in EGFR-mutated non-small-cell lung cancer. , 2015, The New England journal of medicine.

[70]  Tomoya Yamaguchi,et al.  NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for cancer cell survival and progression. , 2013, Cancer cell.

[71]  Scott E. Kern,et al.  Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis , 2011, Nature.

[72]  Joshua F. McMichael,et al.  Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing , 2011, Nature.

[73]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[74]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[75]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[76]  Tsutomu Ohta,et al.  Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy , 2008, Proceedings of the National Academy of Sciences.

[77]  Benjamin J. Raphael,et al.  Mutational landscape and significance across 12 major cancer types , 2013, Nature.

[78]  Li Ding,et al.  Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-Smokers , 2012, Cell.

[79]  D. Bar-Sagi,et al.  RAS oncogenes: weaving a tumorigenic web , 2011, Nature Reviews Cancer.

[80]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[81]  Z. Szallasi,et al.  Spatial and temporal diversity in genomic instability processes defines lung cancer evolution , 2014, Science.

[82]  Jun Ma,et al.  Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. , 2011, The Lancet. Oncology.

[83]  Derek Y. Chiang,et al.  Characterizing the cancer genome in lung adenocarcinoma , 2007, Nature.

[84]  Jeffrey W. Clark,et al.  Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK) inhibitor, in a non-small cell lung cancer patient with de novo MET amplification. , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[85]  G. Getz,et al.  A Genomics-Based Classification of Human Lung Tumors , 2013, Science Translational Medicine.

[86]  Janakiraman Subramanian,et al.  Lung cancer in never smokers: a review. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[87]  F. Cardoso,et al.  Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[88]  Nathan E Hall,et al.  Exploring the utility of human DNA methylation arrays for profiling mouse genomic DNA. , 2013, Genomics.

[89]  R. Young,et al.  BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc , 2011, Cell.

[90]  A. Sivachenko,et al.  A Landscape of Driver Mutations in Melanoma , 2012, Cell.

[91]  John V Heymach,et al.  Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. , 2012, Journal of the National Cancer Institute.

[92]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[93]  A. Adjei,et al.  Small cell lung cancer. , 2008, Mayo Clinic proceedings.

[94]  W. Pao,et al.  Acquired resistance to TKIs in solid tumours: learning from lung cancer , 2014, Nature Reviews Clinical Oncology.

[95]  S. Peters,et al.  Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[96]  William Pao,et al.  Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. , 2014, JAMA.

[97]  S. McMahon,et al.  Analysis of genomic targets reveals complex functions of MYC , 2004, Nature Reviews Cancer.