Deciphering intra-tumor heterogeneity of lung adenocarcinoma confirms that dominant, branching, and private gene mutations occur within individual tumor nodules.

作者: Giuseppe Pelosi , Alessio Pellegrinelli , Alessandra Fabbri , Elena Tamborini , Federica Perrone

DOI: 10.1007/S00428-016-1931-Z

关键词: Tumor progressionKRASSomatic evolution in cancerPTENCancer researchGene mutationAdenocarcinomaWild typeBiologyPathologyMutation

摘要: While pulmonary adenocarcinoma (ADC) is morphologically heterogeneous, little known about intra-tumor gene mutation heterogeneity (ITH). We therefore subjected 20 ADC nodules, 5 mutated for EGFR and KRAS, with an ALK translocation, wild type (WT) these alterations, to unsupervised next-generation sequencing of tumor regions from diverse architectural patterns. When 2 or more different mutations were found in a single tumor, this fulfilled the criteria ITH. In 84 studied architecture, 71 34 WT profiles found. ITH was observed 9/15 (60 %) ADC, 3 EGFR, aberration, as reflected 5, 6, 9 additional mutations, respectively, detected tumors. 21/22 KRAS 18/22 regions, suggesting that they appear early have driver role (dominant trunk mutations). Branching (in EZH2, PIK3CA, TP53, exon 18) occurred two while private ABL1, ALK, BRAF, HER2, KDR, LKB1, PTEN, MET, SMAD4, SMARCB1, SRC) confined unique samples individual lesions, later on during progression. Patients showing branching ran worse clinical course, independent confounding factors. conclude exists pattern spatial temporal hierarchy dominant, branching, mutations. This consistent clonal evolution, which has potential implications patient prognosis development secondary therapy resistance.

参考文章(76)
William D. Travis, Pathology and genetics of tumours of the lung , pleura, thymus and heart Published in <b>2004</b> in Lyon by IARC. ,(2004)
William D. Travis, WHO classification of tumours of the lung, pleura, thymus and heart International Agency for Research on Cancer. ,(2015)
Francesco Zappa, Giovanna Schiavone, Luciano Wannesson, Paola Antonelli, Piera Balzarini, Fausto Sessa, Luca Mazzucchelli, Maria Grazia Tibiletti, Vittoria Martin, Nora Sahnane, Milo Frattini, Barbara Bernasconi, EGFR and KRAS Mutations in ALK-Positive Lung Adenocarcinomas: Biological and Clinical Effect. Clinical Lung Cancer. ,vol. 17, pp. 56- 61 ,(2016) , 10.1016/J.CLLC.2015.08.001
Mats Nilsson, Ida Grundberg, Sara Kiflemariam, Marco Mignardi, Juliana Imgenberg-Kreuz, Karolina Edlund, Patrick Micke, Magnus Sundström, Tobias Sjöblom, Johan Botling, In situ mutation detection and visualization of intratumor heterogeneity for cancer research and diagnostics Oncotarget. ,vol. 4, pp. 2407- 2418 ,(2013) , 10.18632/ONCOTARGET.1527
, A genomics-based classification of human lung tumors Science Translational Medicine. ,vol. 5, pp. 1- 28 ,(2013) , 10.1126/SCITRANSLMED.3006802
TNM classification of malignant tumours Published in <b>2010</b> in Chichester, West Sussex, UK ;Hoboken, NJ by Wiley-Blackwell. ,(1987) , 10.1007/978-3-642-82982-6
Kyu-Tae Kim, Hye Won Lee, Hae-Ock Lee, Sang Cheol Kim, Yun Jee Seo, Woosung Chung, Hye Hyeon Eum, Do-Hyun Nam, Junhyong Kim, Kyeung Min Joo, Woong-Yang Park, None, Single-cell mRNA sequencing identifies subclonal heterogeneity in anti-cancer drug responses of lung adenocarcinoma cells Genome Biology. ,vol. 16, pp. 127- 127 ,(2015) , 10.1186/S13059-015-0692-3
Gavin M. Wright, Hongdo Do, Jonathan Weiss, Naveed Z. Alam, Vivek Rathi, Marzena Walkiewicz, Thomas John, Prudence A. Russell, Alexander Dobrovic, Mapping of actionable mutations to histological subtype domains in lung adenocarcinoma: implications for precision medicine Oncotarget. ,vol. 5, pp. 2107- 2115 ,(2014) , 10.18632/ONCOTARGET.1840
William D Travis, Elisabeth Brambilla, Allen P Burke, Alexander Marx, Andrew G Nicholson, None, Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. Journal of Thoracic Oncology. ,vol. 10, pp. 1240- 1242 ,(2015) , 10.1097/JTO.0000000000000663