School of Biological Sciences, Washington State University, Pullman, Washington 99164
Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138.
Genetics. 2020 Aug;215(4):1143-1152. doi: 10.1534/genetics.120.303428. Epub 2020 Jun 18.
Spontaneous tumor regression has been documented in a small proportion of human cancer patients, but the specific mechanisms underlying tumor regression without treatment are not well understood. Tasmanian devils are threatened with extinction from a transmissible cancer due to universal susceptibility and a near 100% case fatality rate. In over 10,000 cases, <20 instances of natural tumor regression have been detected. Previous work in this system has focused on Tasmanian devil genetic variation associated with the regression phenotype. Here, we used comparative and functional genomics to identify tumor genetic variation associated with tumor regression. We show that a single point mutation in the 5' untranslated region of the putative tumor suppressor significantly contributes to tumor regression. was expressed in regressed tumors but silenced in wild-type, nonregressed tumors, consistent with downregulation in human cancers. Induced expression significantly reduced tumor cell proliferation The RAS pathway is frequently altered in human cancers, and activation may provide a therapeutic treatment option for Tasmanian devils as well as a general mechanism for tumor inhibition.
自发性肿瘤消退已在一小部分人类癌症患者中得到证实，但未经治疗的肿瘤消退的确切机制尚不清楚。由于普遍易感性和接近 100%的病死率，塔斯马尼亚恶魔正面临着一种传染性癌症的灭绝威胁。在超过 10000 例病例中，仅检测到不到 20 例自然肿瘤消退的情况。该系统之前的工作重点是与回归表型相关的塔斯马尼亚恶魔遗传变异。在这里，我们使用比较和功能基因组学来鉴定与肿瘤消退相关的肿瘤遗传变异。我们表明，假定肿瘤抑制因子的 5'非翻译区中的单个点突变 显著促进了肿瘤消退。 在消退的肿瘤中表达，但在野生型、未消退的肿瘤中沉默，这与人类癌症中 的下调一致。诱导 表达显著降低了肿瘤细胞的增殖。 RAS 途径在人类癌症中经常发生改变，而 的激活可能为塔斯马尼亚恶魔提供一种治疗选择，同时也是一种抑制肿瘤的一般机制。
