The Lung Cancer Molecular Disease Model

Lisandra West(1), Smruti J. Vidwans(1), Nicholas P. Campbell(2), Jeff Shrager(1,3), George R. Simon(4), Raphael Bueno(5), Phillip A. Dennis(6), Gregory A. Otterson(7), Ravi Salgia(2)

(1) CollabRx Inc., Palo Alto, California, United States of America, (2) Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, Illinois, United States of America, (3) Symbolic Systems Program (Consulting), Stanford University, Stanford, California, United States of America, (4) Department of Medicine, Section of Hematology/Oncology, Medical University of South Carolina, Charleston, South Carolina, United States of America, (5) Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts, United States of America, (6) National Cancer Institute, Bethesda, Maryland, United States of America, (7) Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America

Lung Cancer Chief Editor: Ravi Salgia, MD, PhD

Lung Cancer Area Editors: Ravi Salgia, MD, PhD, Raphael Bueno, MD, Ross Camidge, MD, PhD, Nicholas Campbell, MD, Sanja Dacic, MD, PhD, Phillip Dennis, MD, PhD, Gregory Otterson, MD, George Simon, MD

Editor in Chief: George D Lundberg

Acknowledgements: We thank Dr. Michelle Turski for help with references, formatting, and organization of the manuscript, and Dr. George Lundberg for ongoing guidance and encouragement.


The initial subtypes and associated practice guidelines defined here were identified by consensus of a panel of recognized lung cancer experts, and supported by detailed analysis of the peer-reviewed scientific literature. Subtypes are defined based on the status of key lung cancer genes/pathways and their combinations. Each subtype is defined by one key oncogene/tumor suppressor (such as EGFR for subtypes 1.1 to 1.3, and KRAS for subtype 2.1), either by itself or in combination with others that play a supportive role (such as EGFR activating mutations in exons 19 and 21 and the exon 20 resistance mutation T790M in the case of subtypes 1.1, 1.2, and 1.3).

These tables summarize the subtypes of lung cancer, roughly in order of importance of the associated oncogene/tumor suppressor, prevalence and potential for therapeutic intervention. The oncogenes that define the subtypes in Table 1 are currently high strength of evidence (SOE) and capable of serving as the dominant oncogene and putative point of intervention for therapy, whereas the oncogenes and tumor suppressor genes that define subtypes in Table 2 are medium or low SOE and on the horizon for lung cancer treatment strategies. These tables also identify the histological subtypes most relevant to each molecular subtype.

Given the evolving state of knowledge, we anticipate this baseline model will need to be revised routinely with new clinical and scientific findings. Existing types are likely to be split into new subtypes corresponding to responders and non-responders, and new types are likely to be added to accommodate previously unseen tumor groups. Over time, this model will be defined with greater and greater specificity and linked to increasingly efficacious therapies.

Click here to read the peer-reviewed Lung Cancer Model paper in PLoS One: West L, Vidwans SJ, Campbell NP, Shrager J, Simon GR, et al. (2012) A Novel Classification of Lung Cancer into Molecular Subtypes. PLoS ONE 7(2): e31906. doi:10.1371/journal.pone.0031906

Table of contents: [click on a section below to read details about that subtype, including drugs, trials, and publications]
Section (subtype) Description
LARGE CELL Large cell lung carcinoma
SCLC Small Cell Lung Cancer
SQUAMOUS Squamous Cell Lung Carcinoma
SUBTYPE 1.1 Activating mutations in the EGFR gene that make these tumors responsive to EGFR 1st gen TKI
SUBTYPE 1.2 NSCLC tumors harboring the T790M mutation
SUBTYPE 1.3 Tumors defined based on a proteomic signature called VeriStrat, which provides likely responsiveness to EGFR inhibitory therapies such as erlotinib in the absence of EGFR mutations
SUBTYPE 2.1 Tumors that have mutations in the KRAS gene
SUBTYPE 3.1 Tumors harboring anaplastic lymphoma kinase (ALK) fusions
SUBTYPE 4.1 Dysregulation of the c-MET pathway leads to cell proliferation, cell survival, angiogenesis, invasion and metastasis. c-MET dysregulation can occur through a variety of mechanisms including c-MET overexpression, activation, overexpression of the c-MET ligand hepatocyte growth factor (HGF), gene amplification, and c-CBL loss of heterozygosity
SUBTYPE 7.1 The ROS-1 translocation is a fusion gene that has been observed predominantly in adenocarcinomas (~1.5%). It is mutually exclusive with mutations in the EGFR, K-ras, and EML4-ALK genes. The ALK inhibitor Xalkori (crizotinib) has been shown to be effective in treating patients with a ROS1 translocation.
SUBTYPE BRAF Tumors that have mutations in the BRAF gene
SUBTYPE HER2 Tumors that have mutations in the HER2 gene
SUBTYPE RET Tumors harboring RET gene fusions
TK1_RESISTANT EGFR mutations, resistant to first generation EGFR 1st gen TKI
Most recent revision released on RELEASE-TTF-2014-10-15


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