Recent progress in mapping the emerging landscape of the small-cell lung cancer genome

Abstract

Small-cell lung cancer (SCLC) remains the deadliest of all the lung cancer types. Its high mortality is largely attributed to the invariable development of resistance to standard chemo/radiotherapies, which have remained unchanged for the past 30 years, underscoring the need for new therapeutic approaches. The discovery of molecular targets for chemoprevention and treatment has been hampered by the poor understanding of SCLC progression. In recent years, comprehensive omics-based analyses have led to the discovery of recurrent alterations in patient tumors, and functional studies using genetically engineered mouse models and patient-derived tumor models have provided information about the alterations critical for SCLC pathogenesis. Defining the somatic alterations scattered throughout the SCLC genome will help to understand the underlying mechanism of this devastating disease and pave the way for the discovery of therapeutic vulnerabilities associated with the genomic alterations.

Fig. 1. Schematic of the integrative approach to identify pathogenetically relevant alterations.

This schematic, modified from George et al., illustrates the process of identifying alterations with a high likelihood of pathological relevance. Candidate alterations extracted from sequencing results are filtered for significant frequency, clustering pattern, damaging nature, and cancer census and further examined for the presence of coherent copy number alterations and run through expression filters (e.g., gene expression or change). Candidate drivers can be directly identified from the analysis of copy number alterations using single nucleotide polymorphism (SNP) arrays or from chimeric transcripts due to gene fusion.

Fig. 2. Graphical summaries of mutations in selected sets of genes.

Each oncoprint, obtained from cBioportal, is a graphical summary of mutations in the potentially related genes across 110 SCLC patient tumors. Although not statistically significant, there are trends toward mutual exclusivity among mutations in TP73, RBL1, and RBL2; CREBBP, EP300, and NOTCH1; and ALMS1 and ASPM.

Fig. 3. A model of epigenetic regulation in the SCLC genome.

This model describes potential interactions among multiple chromatin modifiers on histone marks in the enhancers and promoters of genes. CREBBP/EP300, KMT2 family proteins, and KDM6A act in opposition to PRC2 on H3K27. PBAF complex proteins, CDH7, and SETD2 also participate in the chromatin modification that results in H3K27 acetylation. This epigenetic regulation may influence the expression of numerous genes that are involved in cell-cell and cell-matrix adhesion and epithelial and neuroendocrine differentiation. Asterisks indicate genes recurrently mutated in SCLC. me methyl group, ac acetyl group.

Fig. 4. Genetically engineered mouse model and a precancerous cell-based model of SCLC.

a The Rb/p53-mutant GEMM displays a stepwise process of tumor development that includes preneoplasia at early stages. The neuroendocrine tumor cells and precancerous cells (preSCs) can be labeled with a lineage-specific marker and isolated using fluorescence-activated cell sorting (FACS). b PreSCs are genetically engineered to mimic patient alterations and tested for tumorigenic potential in multiple in vitro and in vivo assays, including allograft models.