Abstract
Lung cancer causes the largest number of cancer-related deaths in the world. Most (85%) of lung cancers are classified as non-small-cell lung cancer (NSCLC) and small-cell lung cancer (15%) (SCLC). The 5-year survival rate for NSCLC patients remains very low (about 16% at 5 years). The two predominant NSCLC histological phenotypes are adenocarcinoma (ADC) and squamous cell carcinoma (LSQCC). ADCs display several recurrent genetic alterations, including: KRAS, BRAF and EGFR mutations; recurrent mutations and amplifications of several oncogenes, including ERBB2, MET, FGFR1 and FGFR2; fusion oncogenes involving ALK, ROS1, Neuregulin1 (NRG1) and RET. In LSQCC recurrent mutations of TP53, FGFR1, FGFR2, FGFR3, DDR2 and genes of the PI3K pathway have been detected, quantitative gene abnormalities of PTEN and CDKN2A. Developments in the characterization of lung cancer molecular abnormalities provided a strong rationale for new therapeutic options and for understanding the mechanisms of drug resistance. However, the complexity of lung cancer genomes is particularly high, as shown by deep-sequencing studies supporting the heterogeneity of lung tumors at cellular level, with sub-clones exhibiting different combinations of mutations. Molecular studies performed on lung tumors during treatment have shown the phenomenon of clonal evolution, thus supporting the occurrence of a temporal tumor heterogeneity.
Highlights
Lung cancer is one of the leading causes of cancer-related deaths in the world
The most significantly focally amplified genes in lung adenocarcinomas are NKX2-1, MYC, TERT, MCL1 and MDM2, while in Lung squamous cell carcinoma (LSQCC) the most amplified were SOX2, CCND1, FGFR1, MYC, YES1, MIR205 and EGFR [43]. Both mutated genes and recurrent somatic copy number alterations are largely distinct for lung adenocarcinomas and LSQCCs [44]. These observations are consistent with gene expression studies showing that while lung adenocarcinoma makes part of a single tumor group composed only by this tumor, LSQCC makes part together with head and neck squamous cancers and with a bladder subtype of one tumor group characterized by TP53 alterations [45]
This study showed that: (a) the analysis of BRAF, EGFR, KRAS, PI3KCA mutations, ALK fusions and FGFR1 amplifications is clinically relevant and helps to define tumor subgroups that can take benefit from patient individualized therapies; the EGFR-mutant lung cancers can be subdivided into two different subgroups according to the presence or absence of TP53 mutations; TP53-mutant tumors can be subdivided into two subgroups, one with RB1 no loss and the other one with RB1 loss [86]
Summary
Lung cancer is one of the leading causes of cancer-related deaths in the world. The five-year lung cancer survival rate is only 15% and lung cancer alone is responsible for more deaths each year than breast, pancreas, colon and prostate cancers together. Other factors contribute to lung cancer development, such as air pollution, indoor emission of fuel burning, environmental exposure to radon, asbestos, some metals such as chromium, cadmium and arsenic and some organic chemicals [5,6] Studies carried out both in Europe and China have provided evidence that particulate matter air pollution contributes to lung cancer incidence [5,6]. This new classification is important because is applicable on resection specimens, and on small biopsies and cytological material [7,8] This is important in view of the fact that about 70% of patients with lung cancer present with advanced stages of disease and are not suitable for tumor resection [7,8]. Metastasis in contralateral hilar or mediastinal lymph nodes, in ipsilateral or contralateral scalene lymph nodes, or in supraclavicular lymph nodes
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