一项基于转座子的小鼠基因筛选鉴定出在结直肠癌中发生改变的基因。
A transposon-based genetic screen in mice identifies genes altered in colorectal cancer.
作者信息
Starr Timothy K, Allaei Raha, Silverstein Kevin A T, Staggs Rodney A, Sarver Aaron L, Bergemann Tracy L, Gupta Mihir, O'Sullivan M Gerard, Matise Ilze, Dupuy Adam J, Collier Lara S, Powers Scott, Oberg Ann L, Asmann Yan W, Thibodeau Stephen N, Tessarollo Lino, Copeland Neal G, Jenkins Nancy A, Cormier Robert T, Largaespada David A
机构信息
Department of Genetics, Cell Biology and Development, Center for Genome Engineering, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
出版信息
Science. 2009 Mar 27;323(5922):1747-50. doi: 10.1126/science.1163040. Epub 2009 Feb 26.
Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.
人类结直肠癌（CRC）表现出大量的基因和表观遗传改变，其中一些与肿瘤发生有因果关系（驱动基因），而另一些则几乎没有功能影响（乘客基因）。为了帮助区分这两类改变，我们在小鼠中使用了基于转座子的基因筛选来鉴定CRC的候选基因。携带诱变型睡美人（SB）转座子的小鼠与在胃肠道上皮中表达SB转座酶的小鼠杂交。大多数后代出现肠道病变，包括上皮内瘤变、腺瘤和腺癌。对超过16000个转座子插入位点的分析确定了77个候选CRC基因，其中60个在人类CRC中发生突变和/或表达失调，因此最有可能驱动肿瘤发生。这些基因包括APC、PTEN和SMAD4。该筛选还确定了17个以前未与CRC相关的候选基因，包括POLI、PTPRK和RSPO2。
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