Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Nat Genet. 2019 Sep;51(9):1308-1314. doi: 10.1038/s41588-019-0475-y. Epub 2019 Aug 12.
Pancreatic ductal adenocarcinoma is an aggressive cancer with limited treatment options. Approximately 10% of cases exhibit familial predisposition, but causative genes are not known in most families. 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 GTPases. 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.
胰腺导管腺癌是一种侵袭性癌症，治疗选择有限。大约 10%的病例表现出家族易感性，但大多数家族中尚未明确致病基因。我们对一个有多例胰腺导管腺癌病例的家族进行了全基因组序列分析，在 RAS 癌基因家族成员 3（RABL3）基因中发现了一个种系截断突变。杂合性 rab13 突变的斑马鱼对癌症形成的敏感性增加。转录组和质谱方法表明 RABL3 参与 RAS 通路调节，并鉴定出与 RAP1GDS1（SmgGDS）的相互作用，SmgGDS 是一种调节 RAS GTP 酶的蛋白前体化的伴侣蛋白。事实上，截短的突变 RABL3 蛋白加速 KRAS 前体化，并需要 RAS 蛋白来促进细胞增殖。最后，在伴有发育障碍的患者队列中的证据表明，胚系 RABL3 突变与 RAS 综合征有关。我们的研究确定 RABL3 突变是癌症家族中进行基因检测的一个靶点，并揭示了发育和癌症中 RAS 活性失调的一种机制。
