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

被引：246

作者：

McFadden, David G. ^{[1
,2
]}

Papagiannakopoulos, Thales ^{[1
,2
]}

Taylor-Weiner, Amaro ^{[4
]}

Stewart, Chip ^{[4
]}

Carter, Scott L. ^{[4
]}

Cibulskis, Kristian ^{[4
]}

Bhutkar, Arjun ^{[1
,2
]}

McKenna, Aaron ^{[4
]}

Dooley, Alison ^{[1
,2
]}

Vernon, Amanda ^{[1
,2
]}

Sougnez, Carrie ^{[4
]}

Malstrom, Scott ^{[1
,2
]}

Heimann, Megan ^{[1
,2
]}

Park, Jennifer ^{[1
,2
]}

Chen, Frances ^{[1
,2
]}

Farago, Anna F. ^{[1
,2
]}

Dayton, Talya ^{[1
,2
]}

Shefler, Erica ^{[4
]}

Gabriel, Stacey ^{[4
]}

Getz, Gad ^{[4
,5
,6
]}

Jacks, Tyler ^{[1
,2
,3
]}

机构：

[1] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA

[2] MIT, Dept Biol, Cambridge, MA 02142 USA

[3] MIT, Howard Hughes Med Inst, Cambridge, MA 02142 USA

[4] Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

CELL | 2014年 / 156卷 / 06期

关键词：

COPY-NUMBER ALTERATION; PTEN TUMOR-SUPPRESSOR; SOMATIC MUTATIONS; MOUSE MODEL; CANCER; EVOLUTION; HETEROGENEITY; INACTIVATION; INSTABILITY; ABERRATIONS;

D O I：

10.1016/j.cell.2014.02.031

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1298 / 1311

页数：14

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