Molecular Evolution Patterns in Metastatic Lymph Nodes Reflect the Differential Treatment Response of Advanced Primary Lung Cancer.

Tumor heterogeneity influences the clinical outcome of patients with cancer, and the diagnostic method to measure the tumor heterogeneity needs to be developed. We analyzed genomic features on pairs of primary and multiple metastatic lymph nodes from six patients with lung cancer using whole-exome sequencing and RNA sequencing. Although somatic single-nucleotide variants were shared in primary lung cancer and metastases, tumor evolution predicted by the pattern of genomic alterations was matched to anatomic location of the tumors. Four of six cases exhibited a branched clonal evolution pattern. Lymph nodes with acquired somatic variants demonstrated resistance to the cancer treatment. In this study, we demonstrated that multiple biopsies and sequencing strategies for different tumor regions are required for a comprehensive understanding of the landscape of genetic alteration and for guiding targeted therapy in advanced primary lung cancer. Cancer Res; 76(22); 6568-76. ©2016 AACR.

[1]  Ming You,et al.  Functional characterization of RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus , 2016, Molecular carcinogenesis.

[2]  J. Mester,et al.  Akt2 knock-down reveals its contribution to human lung cancer cell proliferation, growth, motility, invasion and endothelial cell tube formation , 2015, Scientific Reports.

[3]  Sean R. Landman,et al.  Transposon Mutagenesis Screen Identifies Potential Lung Cancer Drivers and CUL3 as a Tumor Suppressor , 2015, Molecular Cancer Research.

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

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

[6]  Paul Theodor Pyl,et al.  HTSeq—a Python framework to work with high-throughput sequencing data , 2014, bioRxiv.

[7]  Charles Swanton,et al.  Deciphering intratumor heterogeneity and temporal acquisition of driver events to refine precision medicine , 2014, Genome Biology.

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

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

[10]  A. Bouchard-Côté,et al.  PyClone: statistical inference of clonal population structure in cancer , 2014, Nature Methods.

[11]  A. Krešo,et al.  Evolution of the cancer stem cell model. , 2014, Cell stem cell.

[12]  M. Brock,et al.  Staging lymph node metastases from lung cancer in the mediastinum. , 2014, Journal of thoracic disease.

[13]  Yan-bin Zhao,et al.  ABCC3 as a marker for multidrug resistance in non-small cell lung cancer , 2013, Scientific Reports.

[14]  E. Hopper-Borge,et al.  Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma , 2013, Journal of cancer research updates.

[15]  B. Giusti,et al.  EXCAVATOR: detecting copy number variants from whole-exome sequencing data , 2013, Genome Biology.

[16]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[17]  K. Capaccione,et al.  The Notch signaling pathway as a mediator of tumor survival. , 2013, Carcinogenesis.

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

[19]  M. Ladanyi,et al.  ALK Rearrangements Are Mutually Exclusive with Mutations in EGFR or KRAS: An Analysis of 1,683 Patients with Non–Small Cell Lung Cancer , 2013, Clinical Cancer Research.

[20]  William Pao,et al.  Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers , 2013, Clinical Cancer Research.

[21]  Giovanni Parmigiani,et al.  Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma , 2012, Nature Genetics.

[22]  Justin Guinney,et al.  GSVA: gene set variation analysis for microarray and RNA-Seq data , 2013, BMC Bioinformatics.

[23]  S. Bosari,et al.  Lymph node micrometastases detected by carcinoembryonic antigen mRNA affect long-term survival and disease-free interval in early-stage lung cancer patients. , 2012, Oncology letters.

[24]  Ying-jian Chen,et al.  Direct serum and tissue assay for EGFR mutation in non-small cell lung cancer by high-resolution melting analysis. , 2012, Oncology reports.

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

[26]  Sung-Liang Yu,et al.  Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[28]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

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

[30]  S. Digumarthy,et al.  Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Zuquan Zou,et al.  A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells. , 2009, International journal of molecular medicine.

[32]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[33]  Y. Ishikawa,et al.  EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset , 2009, Modern Pathology.

[34]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

[35]  Derek Y. Chiang,et al.  EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer , 2008, Clinical Cancer Research.

[36]  H. Aburatani,et al.  Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer , 2007, Nature.

[37]  J. Testa,et al.  Perturbations of the AKT signaling pathway in human cancer , 2005, Oncogene.

[38]  P. Vogt,et al.  Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  J. Testa,et al.  Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. , 2004, Carcinogenesis.

[40]  S. Baylin,et al.  Notch signaling induces cell cycle arrest in small cell lung cancer cells. , 2001, Cancer research.

[41]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[42]  H. Libshitz,et al.  Patterns of mediastinal metastases in bronchogenic carcinoma. , 1986, Chest.