Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells

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.

Keywords: cancer stem cells; genomic profiling; membrane cell markers; non-small cell lung cancer; small cell lung cancer; tumor xenotransplantation assay.

Figure 1

(A) Comparison of the most recurrent gene mutations in lung adenocarcinoma between Caucasians and EAST Asians; (B) Various gene mutations at the level of the EGFR gene in Caucasians and East Asians; (C) Various gene mutations at the level of the KRAS gene in Caucasians and East Asians. Data are reported in [13,17].

Figure 2

Frequency of main genetic alterations, subdivided into various levels according to the degree of therapeutic actionability of genetic events, in two groups of lung adenocarcinoma patients: TCGA data sets based on the analysis of non-metastatic patients and MSK-IMPAC data based on the analysis of recurrent/metastatic lung adenocarcinomas. Date are reported in [13,19].

Figure 3

Pattern of frequently altered genes in LSQCC and HNSCC, subdivided according to their biologic function. A: Cell Survival; B: Squamous Cell Differentiation; C. Chromatin Transcription Gene Expression; D: Cell Cycle Control; E: Mitogenesis, RAS Signaling. Data are reported in [85].

Figure 4

Genetic abnormalities observed in neuroendocrine lung cancers classified into four subtypes: TC (Typical Carcinoid); AC (Atypical Carcinoid); LCNEC (Large Cell Neuro Endocrine Carcinoma); SCLC (Small Cell Lung Carcinoma). A: Copy Number Alterations; B: Gene Mutations The data plotted in this figure were reported by Simbolo et al. [123].

Figure 5

(A) Age distribution at diagnosis of Chinese NSCLC patients with ALK-EML4 rearrangements, EGFR mutations and wild type (without ALK or EGFR alterations) tumors; (B) age distribution of ALK-rearranged NSCLCs stratified by smoking status; (C) age distribution of EGFR-mutant NSCLCs stratified by smoking status.