美国哈佛医学院Wolfram Goessling课题组取得一项新进展，他们发现RABL3基因的突变改变了KRAS异戊二烯化修饰并且与遗传性胰腺癌相关。相关论文2019年9月发表于国际学术期刊《自然—遗传学》。

研究人员在具有多个胰腺导管腺癌病例的家族中进行全基因组序列分析，并在RAS癌基因家族样3（RABL3）基因的成员中鉴定种系截短突变。杂合的rabl3突变体斑马鱼表现出癌症形成的易感性增加。转录组学和质谱法方法提示RABL3在RAS途径调节中并鉴定与RAP1GDS1（SmgGDS）的相互作用，RAP1GDS1是一种调节RAS GTPases 3异戊二烯化修饰的分子伴侣。实际上，截短的突变体RABL3蛋白加速KRAS异戊烯化并且需要RAS蛋白促进细胞增殖。最后，患有发育障碍的患者队列中的证据表明RASopathy综合征中存在RABL3的生殖突变。这些研究将RABL3突变鉴定为癌症家族中基因检测的靶标，并揭示了发育和癌症中RAS活性失调的机制。

据了解，胰腺导管腺癌是一种侵袭性癌症，并且治疗手段有限。大约10％的病例表现出家族性倾向，但大多数家庭都不知道致病基因。

附：英文原文

Title: Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer

Author: Sahar Nissim, Ignaty Leshchiner, Joseph D. Mancias, Matthew B. Greenblatt, Ophlia Maertens, Christopher A. Cassa, Jill A. Rosenfeld, Andrew G. Cox, John Hedgepeth, Julia I. Wucherpfennig, Andrew J. Kim, Jake E. Henderson, Patrick Gonyo, Anthony Brandt, Ellen Lorimer, Bethany Unger, Jeremy W. Prokop, Jerry R. Heidel, Xiao-Xu Wang, Chinedu I. Ukaegbu, Benjamin C. Jennings, Joao A. Paulo, Sebastian Gableske, Carol A. Fierke, Gad Getz, Shamil R. Sunyaev, J. Wade Harper, Karen Cichowski, Alec C. Kimmelman, Yariv Houvras, Sapna Syngal, Carol Williams, Wolfram Goessling

Issue&Volume: Volume 51 Issue 9

Abstract: Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options1. Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families2. We perform whole-genome sequence analysis in a family with multiple cases of pancreatic ductal adenocarcinoma and identify a germline truncating mutation in the member of the RAS oncogene family-like 3 (RABL3) gene. Heterozygous rabl3 mutant zebrafish show increased susceptibility to cancer formation. Transcriptomic and mass spectrometry approaches implicate RABL3 in RAS pathway regulation and identify an interaction with RAP1GDS1 (SmgGDS), a chaperone regulating prenylation of RAS GTPases3. Indeed, the truncated mutant RABL3 protein accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Finally, evidence in patient cohorts with developmental disorders implicates germline RABL3 mutations in RASopathy syndromes. Our studies identify RABL3 mutations as a target for genetic testing in cancer families and uncover a mechanism for dysregulated RAS activity in development and cancer.

DOI: 10.1038/s41588-019-0475-y

Source: https://www.nature.com/articles/s41588-019-0475-y