Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing

Abstract

Summary Small cell lung carcinoma (SCLC) is a highly lethal, smoking-associated cancer with few known targetable genetic alterations. Using genome sequencing, we characterized the somatic evolution of a genetically engineered mouse model (GEMM) of SCLC initiated by loss of Trp53 and Rb1. We identified alterations in DNA copy number and complex genomic rearrangements and demonstrated a low somatic point mutation frequency in the absence of tobacco mutagens. Alterations targeting the tumor suppressor Pten occurred in the majority of murine SCLC studied, and engineered Pten deletion accelerated murine SCLC and abrogated loss of Chr19 in Trp53; Rb1; Pten compound mutant tumors. Finally, we found evidence for polyclonal and sequential metastatic spread of murine SCLC by comparative sequencing of families of related primary tumors and metastases. We propose a temporal model of SCLC tumorigenesis with implications for human SCLC therapeutics and the nature of cancer-genome evolution in GEMMs.

Distinctive properties of metastasis-initiating cells

“…However, recent studies using lineage tracing, barcode sequencing, and whole-genome sequencing are shedding light on this question and have demonstrated a mostly polyclonal nature of metastasis (Fig. 5;McFadden et al 2014;Gundem et al 2015;Maddipati and Stanger 2015;Wagenblast et al 2015).…”

“…Mutation analysis between the primary tumor and the metastatic lesions indicated polyclonal metastatic spread in the lymph nodes but not in the liver (McFadden et al 2014). Another whole-genome sequencing study analyzed 51 tumors of 10 prostate cancer patients, including primary tumors and multiple metastases in the same patients, and revealed the coexistence of multiple clones in the metastases, including those from metastasis-to-metastasis spreads (Gundem et al 2015).…”

“…In the past few years, new and emerging technologies have begun to enable the study of MICs in animal and clinical models. Genomic sequencing studies have provided genome-wide comparisons between primary tumors and matched distant metastases from cancer patients and animal models (Campbell et al 2010;Yachida et al 2010;McFadden et al 2014;Gundem et al 2015). Gene expression analysis at the single-cell level has become a powerful tool to analyze the population dynamics of tumor cells during metastatic evolution (Lawson et al 2015).…”

A general framework for analyzing tumor subclonality using SNP array and DNA sequencing data

“…Similarly, multi-region comparisons have revealed extensive genomic variability across different geographic sectors of the tumor [33,34], or between the primary and metastatic tumors [35]. These studies, while using samples collected with a higher spatial or temporal resolution than those in TCGA and ICGC, often still contain heterogeneous populations of cells [35][36][37].…”

Chemotherapy-Regulated microRNA-125–HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer

“…In the meantime, the therapeutic strategy for SCLC has remained as platinum-based combination chemotherapy for the last several decades (4). Although a few recent SCLC sequencing studies have reported novel putative driver gene alterations, specific moleculartargeting therapy against such alteration is not yet available (5)(6)(7).…”