Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.,Nature Genetics

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Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.
Nature Genetics ( IF 31.7 ) Pub Date : 2019-08-12 , DOI: 10.1038/s41588-019-0475-y
Sahar Nissim _{1,

2,

3,

4} , Ignaty Leshchiner _{2,

5} , Joseph D Mancias _{3,

6} , Matthew B Greenblatt ₇ , Ophélia Maertens ₂ , Christopher A Cassa ₂ , Jill A Rosenfeld ₈ , Andrew G Cox _{9,

10} , John Hedgepeth ₂ , Julia I Wucherpfennig ₂ , Andrew J Kim ₂ , Jake E Henderson ₂ , Patrick Gonyo ₁₁ , Anthony Brandt ₁₁ , Ellen Lorimer ₁₁ , Bethany Unger ₁₁ , Jeremy W Prokop ₁₂ , Jerry R Heidel ₁₃ , Xiao-Xu Wang ₃ , Chinedu I Ukaegbu ₃ , Benjamin C Jennings ₁₄ , Joao A Paulo ₆ , Sebastian Gableske ₃ , Carol A Fierke ₁₄ , Gad Getz _{5,

15} , Shamil R Sunyaev _{2,

16} , J Wade Harper ₆ , Karen Cichowski _{2,

3} , Alec C Kimmelman ₁₇ , Yariv Houvras ₁₈ , Sapna Syngal _{1,

3} , Carol Williams ₁₁ , Wolfram Goessling _{2,

3,

4,

5,

19,

20}

Affiliation

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.
Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Department of Pathology and Laboratory Medicine and the Hospital for Special Surgery, Weill Cornell Medical College, Cornell University, New York, NY, USA.
The Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
Cancer Center and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Carlson College of Veterinary Medicine, Oregon State University, Corvallis, OR, USA.
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Cancer Center and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Department of Radiation Oncology, Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
Weill Cornell Medical College and New York Presbyterian Hospital, New York, NY, USA.
Harvard Stem Cell Institute, Cambridge, MA, USA.
Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

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.

中文翻译：

RABL3 的突变会改变 KRAS 异戊二烯化并与遗传性胰腺癌有关。

胰腺导管腺癌是一种侵袭性癌症，治疗选择有限1。大约 10% 的病例表现出家族倾向，但大多数家族的致病基因尚不清楚。我们对一个患有多例胰腺导管腺癌的家族进行了全基因组序列分析，并在 RAS 癌基因家族样 3 (RABL3) 基因的成员中鉴定了一个生殖系截短突变。杂合 rabl3 突变斑马鱼对癌症形成的易感性增加。转录组学和质谱方法将 RABL3 与 RAS 通路调节联系起来，并确定与 RAP1GDS1 (SmgGDS) 的相互作用，RAP1GDS1 (SmgGDS) 是一种调节 RAS GTPase3 异戊二烯化的伴侣。实际上，截短的突变 RABL3 蛋白加速了 KRAS 异戊二烯化并需要 RAS 蛋白来促进细胞增殖。最后，患有发育障碍的患者队列中的证据表明 RASopathy 综合征中的胚系 RABL3 突变。我们的研究将 RABL3 突变确定为癌症家族基因检测的目标，并揭示了发育和癌症中 RAS 活性失调的机制。

更新日期：2019-08-12

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