A Novel Classification of Lung Cancer into Molecular Subtypes

West, Lisandra; Vidwans, Smruti J.; Campbell, Nicholas; Shrager, Jeff; Simon, George R.; Bueno, Raphael; Dennis, Phillip A.; Otterson, Gregory A.; Salgia, Ravi

doi:10.1371/journal.pone.0031906

Cited by 110 publications

(96 citation statements)

References 86 publications

(160 reference statements)

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“…Western blotting confirmed that SKI is often coexpressed with SOX2, OCT4 and KLF4 (Supplementary Figure 7). Considering the fact that, pathologically, lung ADCs carrying Kras and p53 mutations are classified as poorly differentiated, high-grade cancers, 38,39 the expression of pluripotency-associated transcription factors indicates that KrasG12D-generated SCCs are composed of cells that are relatively immature.…”

Section: Resultsmentioning

confidence: 99%

Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

et al. 2014

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Identification of target cells in lung tumorigenesis and characterization of the signals that control their behavior is an important step toward improving early cancer diagnosis and predicting tumor behavior. We identified a population of cells in the adult lung that bear the EpCAM þ CD104 þ CD49f þ CD44 þ CD24loSCA1 þ phenotype and can be clonally expanded in culture, consistent with the properties of early progenitor cells. We show that these cells, rather than being restricted to one tumor type, can give rise to several different types of cancer, including adenocarcinoma and squamous cell carcinoma. We further demonstrate that these cells can be converted from one cancer type to the other, and this plasticity is determined by their responsiveness to transforming growth factor (TGF)-beta signaling. Our data establish a mechanistic link between TGF-beta signaling and SOX2 expression, and identify the TGF-beta/SMAD/SOX2 signaling network as a key regulator of lineage commitment and differentiation of lung cancer cells. Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. Lung cancers are divided into two major categories: non-small-cell lung cancer (NSCLC) and small-cell lung cancer. NSCLC accounts for B80% of all lung cancers and is divided further into adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large-cell lung carcinoma. Of the four major types of lung cancer, Kras mutations are present in about 30-50% of ADC, a smaller percentage of SCC (5-7%) and o1% of SCLC.

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Section: Resultsmentioning

confidence: 99%

Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

et al. 2014

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“…Most cases of lung cancer are diagnosed at advanced stages, with stage IV associated with a 1% 5-year survival rate (1). In the past decade, molecular "driver" mutations have been identified, and small-molecule kinase inhibitors have been developed to target specific molecular aberrations (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation–Positive Non–Small Cell Lung Cancer

Kazandjian

Blumenthal

Yuan

et al. 2016

Clinical Cancer Research

199

130

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On July 13, 2015, the FDA approved gefitinib (Iressa; AstraZeneca UK Limited) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test. Concurrently, a labeling expansion of the therascreen EGFR RGQ PCR Kit (Qiagen) as a companion diagnostic test was approved. The approval was based on the results of a multicenter, single-arm, open-label clinical study of 106 treatment-na€ ve patients with metastatic EGFR mutation-positive NSCLC who received gefitinib, 250 mg daily, until disease progression or intolerable toxicity. The major efficacy outcome was RECIST v1.1 objective response rate (ORR). The blinded independent central review (BICR) ORR was 50% [95% confidence interval (CI), 41-59] with a median duration of response (DoR) of 6.0 months. Efficacy results were supported by a retrospective exploratory analysis of a subset of a randomized, multicenter, open-label trial on 1,217 patients with metastatic NSCLC. Of the patients randomized, 186 (15%) were retrospectively determined to be EGFR positive and evaluable for a BICR assessment. The HR for progression-free survival (PFS) was 0.54 (95% CI, 0.38-0.79), favoring gefitinib over platinum-doublet chemotherapy. The most common (20%) adverse reactions were skin reactions, increased aspartate and alanine aminotransferase, proteinuria, and diarrhea. Approximately 5% of patients discontinued treatment due to an adverse reaction. Given the safety profile and clinically meaningful ORR, DoR, and PFS, the benefit-risk analysis was deemed favorable for FDA approval.

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“…In addition, inactivating mutations in NOTCH family genes have been identified by whole-genome sequencing in 25% of human SCLC tumors, suggesting that these alterations may represent a major feature of SCLC (25) . NOTCH signaling is critical in the regulation of the neuroendocrine compartment size in the maturaation of lung and its inactivation could therefore contribute to malignant transformation of neuroendocrine cells (2,(27)(28)(29)(30) .…”

Section: Major Molecular Alterations In Lung Cancersmentioning

confidence: 99%

Histopathological and molecular features of lung cancer

Diniz¹,

Ünlü²,

Kömürcüoğlu³

2017

Terh

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Lung cancer has been more frequently observed during the last 70 years. Many factors thought to be of pathogenic importance in the past are now considered to be totally unrelated or minimally related to cancer. The exposure to asbestosis, polycyclic aromatic hydrocarbons, nickel, arsenic, radon, and vinyl chloride are also responsible for carcinomas. But all of these factors become extremely unimportant when compared with the role played by smoking. Tobacco has a long history dating back to 600 A.D. It is known that Native Americans smoked tobacco for special religious and medical purposes. In 1964, the first report was published about the dangers of smoking and it was noticed that the nicotine and tar in cigarettes cause lung cancer. It is currently known that the smoke contains high levels of carcinogenic tobacco-specific nitrosamines. Therefore lung tumors that are histologically similar to the smoking-related lung cancers in humans do not develop in "non-smoker" animals. Most cases of lung cancer are most frequently diagnosed at an advanced stage where only limited number of treatment alternatives can be offered to these patients. The development of lung cancer involves multiple phases of tumorigenesis including interactions among genetic, epigenetic, and environmental factors with resultant dysregulation of key oncogenes and tumor suppressor genes ending in activation of cancer-related signaling pathways. For years, lung cancers have been classified as small cell and non-small cell lung cancers and this classification was satisfactory for treatment. The past decade has witnessed the discovery of multiple molecules that are effective in the development of lung cancer which are more commonly detected in adenocarcinomas. Therefore in histopathological examination, special aim is placed on discriminating adenocarcinomas from the other lung cancers so as to effectively select tumors for targeted molecular testing. Current review summarizes the histopathological features of lung cancers according to the 2015 World Health Organization (WHO) classification of lung cancer and attempts to focus on further understanding of the molecular abnormalities underlying lung cancer development and progression.

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A Novel Classification of Lung Cancer into Molecular Subtypes

Cited by 110 publications

References 86 publications

Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

Transforming growth factor-beta signaling network regulates plasticity and lineage commitment of lung cancer cells

FDA Approval of Gefitinib for the Treatment of Patients with Metastatic EGFR Mutation–Positive Non–Small Cell Lung Cancer

Histopathological and molecular features of lung cancer

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