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

Sahar Nissim; Ignaty Leshchiner; Joseph D. Mancias; Matthew B. Greenblatt; Ophélia 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

doi:10.1038/s41588-019-0475-y

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

Sahar Nissim, Ignaty Leshchiner, Joseph D. Mancias, Matthew B. Greenblatt, Ophélia 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. UkaegbuBenjamin 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

Division of Hematology

Research output: Contribution to journal › Letter › peer-review

35 Scopus citations

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.

Original language	English
Pages (from-to)	1308-1314
Number of pages	7
Journal	Nature Genetics
Volume	51
Issue number	9
DOIs	https://doi.org/10.1038/s41588-019-0475-y
State	Published - Sep 1 2019

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Nissim, S., Leshchiner, I., Mancias, J. D., Greenblatt, M. B., Maertens, O., Cassa, C. A., Rosenfeld, J. A., Cox, A. G., Hedgepeth, J., Wucherpfennig, J. I., Kim, A. J., Henderson, J. E., Gonyo, P., Brandt, A., Lorimer, E., Unger, B., Prokop, J. W., Heidel, J. R., Wang, X. X., ... Goessling, W. (2019). Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer. Nature Genetics, 51(9), 1308-1314. https://doi.org/10.1038/s41588-019-0475-y

@article{1823f3530f144369809d4ba56baddb00,

title = "Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer",

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.",

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

note = "Funding Information: This work was supported by the NIH grant nos. K08 DK105326 (to S.N.); R01 DK090311, R01 DK095721 and R24 OD017870 (to W.G.); R01 GM095567, R01 CA157490, R01 CA188048, P01 CA117969 and R35 CA232124 (to A.C.K.); R01 CA188871 (to C.W.) and R01 GM040602 (to C.A.F.); as well as grants from the National Pancreas Foundation (to S.N.), the Harvard Digestive Diseases Center (grant no. P30 DK034854 to S.N. and W.G.), the Ken and Louise Goldberg Award (to S.N.), an ACS Research Scholar Grant (RSG-13-298-01-TBG to A.C.K.), the Lustgarten Foundation and SU2C (to A.C.K) and the Anna Fuller Fund and the Claudia Adams Barr Program for Innovative Cancer Research (to W.G.). S.N. is a recipient of the Burroughs Wellcome Fund Career Award for Medical Scientists. W.G. is a Pew Scholar in the Biomedical Sciences. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = sep,

day = "1",

doi = "10.1038/s41588-019-0475-y",

language = "English",

volume = "51",

pages = "1308--1314",

journal = "Nature Genetics",

issn = "1061-4036",

number = "9",

}

Nissim, S, Leshchiner, I, Mancias, JD, Greenblatt, MB, Maertens, O, Cassa, CA, Rosenfeld, JA, Cox, AG, Hedgepeth, J, Wucherpfennig, JI, Kim, AJ, Henderson, JE, Gonyo, P, Brandt, A, Lorimer, E, Unger, B, Prokop, JW, Heidel, JR, Wang, XX, Ukaegbu, CI, Jennings, BC, Paulo, JA, Gableske, S, Fierke, CA, Getz, G, Sunyaev, SR, Wade Harper, J, Cichowski, K, Kimmelman, AC, Houvras, Y, Syngal, S, Williams, C & Goessling, W 2019, 'Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer', Nature Genetics, vol. 51, no. 9, pp. 1308-1314. https://doi.org/10.1038/s41588-019-0475-y

TY - JOUR

T1 - Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer

AU - Nissim, Sahar

AU - Leshchiner, Ignaty

AU - Mancias, Joseph D.

AU - Greenblatt, Matthew B.

AU - Maertens, Ophélia

AU - Cassa, Christopher A.

AU - Rosenfeld, Jill A.

AU - Cox, Andrew G.

AU - Hedgepeth, John

AU - Wucherpfennig, Julia I.

AU - Kim, Andrew J.

AU - Henderson, Jake E.

AU - Gonyo, Patrick

AU - Brandt, Anthony

AU - Lorimer, Ellen

AU - Unger, Bethany

AU - Prokop, Jeremy W.

AU - Heidel, Jerry R.

AU - Wang, Xiao Xu

AU - Ukaegbu, Chinedu I.

AU - Jennings, Benjamin C.

AU - Paulo, Joao A.

AU - Gableske, Sebastian

AU - Fierke, Carol A.

AU - Getz, Gad

AU - Sunyaev, Shamil R.

AU - Wade Harper, J.

AU - Cichowski, Karen

AU - Kimmelman, Alec C.

AU - Houvras, Yariv

AU - Syngal, Sapna

AU - Williams, Carol

AU - Goessling, Wolfram

N1 - Funding Information: This work was supported by the NIH grant nos. K08 DK105326 (to S.N.); R01 DK090311, R01 DK095721 and R24 OD017870 (to W.G.); R01 GM095567, R01 CA157490, R01 CA188048, P01 CA117969 and R35 CA232124 (to A.C.K.); R01 CA188871 (to C.W.) and R01 GM040602 (to C.A.F.); as well as grants from the National Pancreas Foundation (to S.N.), the Harvard Digestive Diseases Center (grant no. P30 DK034854 to S.N. and W.G.), the Ken and Louise Goldberg Award (to S.N.), an ACS Research Scholar Grant (RSG-13-298-01-TBG to A.C.K.), the Lustgarten Foundation and SU2C (to A.C.K) and the Anna Fuller Fund and the Claudia Adams Barr Program for Innovative Cancer Research (to W.G.). S.N. is a recipient of the Burroughs Wellcome Fund Career Award for Medical Scientists. W.G. is a Pew Scholar in the Biomedical Sciences. Publisher Copyright: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85070822684&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0475-y

DO - 10.1038/s41588-019-0475-y

M3 - Letter

C2 - 31406347

AN - SCOPUS:85070822684

VL - 51

SP - 1308

EP - 1314

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 9

ER -

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

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