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

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• 作者：David G. McFadden¹ ; ⁵ ; Thales Papagiannakopoulos¹ ; ⁵ ; Amaro Taylor-Weiner³ ; ⁵ ; Chip Stewart³ ; ⁵ ; Scott L. Carter³ ; ⁵ ; Kristian Cibulskis³ ; Arjun Bhutkar¹ ; Aaron McKenna³ ; Alison Dooley¹ ; Amanda Vernon¹ ; Carrie Sougnez³ ; Scott Malstrom¹ ; Megan Heimann¹ ; Jennifer Park¹ ; Frances Chen¹ ; Anna F. Farago¹ ; Talya Dayton¹ ; Erica Shefler³ ; Stacey Gabriel³ ; Gad Getz³ ; ⁴ ; ^{gadgetz@broadinstitute.org" class="auth_mail} ; Tyler Jacks¹ ; ² ; ^{tjacks@mit.edu" class="auth_mail}
• 刊名：Cell
• 出版年：13 March, 2014
• 年：2014
• 卷：156
• 期：6
• 页码：1298-1311
• 全文大小：3322 K

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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.