Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Nat Genet. 2010 Mar;42(3):216-23. doi: 10.1038/ng.527. Epub 2010 Feb 7.
Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor.
全基因组分析人类肺腺癌已鉴定出一致的拷贝数增益或缺失区域，但在许多情况下，假定位于这些基因座中的癌基因和肿瘤抑制基因仍有待确定。在这里，我们鉴定出下游酪氨酸激酶 (Dok) 家族成员 Dok1、Dok2 和 Dok3 为肺肿瘤抑制基因。这些基因在小鼠中的单一、双重或三重缺失会导致肺癌，其外显率和潜伏期取决于丢失的 Dok 等位基因的数量。在癌症发展之前，肺泡 II 型细胞和细支气管肺泡干细胞出现异常扩张和信号转导特征。在人类肺腺癌中，我们鉴定出 DOK2 是拷贝数缺失和 mRNA 下调的靶点，并发现 DOK2 抑制体外和体内肺癌细胞的增殖。鉴于 DOK2 的基因组定位，我们提出它是 8p21.3 杂合不足的人类肺肿瘤抑制基因。
