Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain

被引：334

作者：

Nikolaev, S. I. ^{[1
,2
]}

Vetiska, S. ^{[4
]}

Bonilla, X. ^{[1
]}

Boudreau, E. ^{[5
,9
,10
]}

Jauhiainen, S. ^{[11
,12
,13
]}

Jahromi, B. Rezai ^{[11
,12
,13
]}

Khyzha, N. ^{[5
,9
,10
]}

DiStefano, P. V. ^{[5
,9
,10
]}

Suutarinen, S. ^{[11
,12
,13
]}

Kiehl, T. -R. ^{[6
,9
]}

Pereira, V. Mendes ^{[7
,8
]}

Herman, A. M. ^{[15
,16
]}

Krings, T. ^{[7
,8
]}

Andrade-Barazarte, H. ^{[7
]}

Tung, T. ^{[7
]}

Valiante, T. ^{[7
]}

Zadeh, G. ^{[7
]}

Tymianski, M. ^{[4
,7
]}

Rauramaa, T. ^{[12
,13
,14
]}

Yla-Herttuala, S. ^{[11
]}

Wythe, J. D. ^{[15
,16
]}

Antonarakis, S. E. ^{[1
,2
,3
]}

Frosen, J. ^{[11
,12
,13
]}

Fish, J. E. ^{[5
,9
,10
]}

Radovanovic, I. ^{[4
,7
]}

机构：

[1] Univ Geneva, Dept Genet Med & Dev, Med Sch, Geneva, Switzerland

[2] Univ Hosp Geneva, Serv Genet Med, Geneva, Switzerland

[3] Inst Genet & Genom Geneva, iGE3, Geneva, Switzerland

[4] Krembil Res Inst, Dept Fundamental Neurobiol, Toronto, ON, Canada

[5] Toronto Gen Hosp, Res Inst, Toronto, ON, Canada

[6] Univ Hlth Network, Toronto Western Hosp, Dept Pathol, Toronto, ON, Canada

[7] Univ Hlth Network, Toronto Western Hosp, Div Neurosurg, Dept Surg, Toronto, ON, Canada

[8] Univ Hlth Network, Toronto Western Hosp, Joint Div Med Imaging, Dept Med Imaging, Toronto, ON, Canada

[9] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[10] Heart & Stroke Richard Lewar Ctr Excellence Cardi, Toronto, ON, Canada

[11] Univ Eastern Finland, Dept Mol Med, AIV Inst, Kuopio, Finland

[12] Kuopio Univ Hosp, Hemorrhag Brain Pathol Res Grp, Dept Neurosurg, Kuopio, Finland

[13] Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland

[14] Kuopio Univ Hosp, Dept Pathol, Kuopio, Finland

[15] Baylor Coll Med, Cardiovasc Res Inst, Houston, TX 77030 USA

[16] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2018年 / 378卷 / 03期

关键词：

VENOUS MALFORMATION; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; GENE; NOTCH; ANGIOGENESIS; PREVALENCE; RECEPTORS; DISEASE; PROTEIN;

D O I：

10.1056/NEJMoa1709449

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRAS(G12V)) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells.

引用

页码：250 / 261

页数：12

共 38 条

[1] Prevalence of adults with brain arteriovenous malformations: a community based study in Scotland using capture-recapture analysis [J].

Al-Shahi, R ;

Fang, JSY ;

Lewis, SC ;

Warlow, CP .

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2002, 73 (05) :547-551

[2] A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults [J].

Al-Shahi, R ;

Warlow, C .

BRAIN, 2001, 124 :1900-1926

[3] Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling [J].

Amyere, Mustapha ;

Revencu, Nicole ;

Helaers, Raphael ;

Pairet, Eleonore ;

Baselga, Eulalia ;

Cordisco, Maria ;

Chung, Wendy ;

Dubois, Josee ;

Lacour, Jean-Philippe ;

Martorell, Loreto ;

Mazereeuw-Hautier, Juliette ;

Pyeritz, Reed E. ;

Amor, David J. ;

Bisdorff, Annouk ;

Blei, Francine ;

Bombei, Hannah ;

Dompmartin, Anne ;

Brooks, David ;

Dupont, Juliette ;

Gonzalez-Enseat, Maria Antonia ;

Frieden, Ilona ;

Gerard, Marion ;

Kvarnung, Malin ;

Hanson-Kahn, Andrea Kwan ;

Hudgins, Louanne ;

Leaute-Labreze, Christine ;

McCuaig, Catherine ;

Metry, Denise ;

Parent, Philippe ;

Paul, Carle ;

Petit, Florence ;

Phan, Alice ;

Quere, Isabelle ;

Salhi, Aicha ;

Turner, Anne ;

Vabres, Pierre ;

Vicente, Asuncion ;

Wargon, Orli ;

Watanabe, Shoji ;

Weibel, Lisa ;

Wilson, Ashley ;

Willing, Marcia ;

Mulliken, John B. ;

Boon, Laurence M. ;

Vikkula, Miikka .

CIRCULATION, 2017, 136 (11) :1037-+

[4] Cancer-Associated Mutations in Endometriosis without Cancer [J].

Anglesio, M. S. ;

Papadopoulos, N. ;

Ayhan, A. ;

Nazeran, T. M. ;

Noe, M. ;

Horlings, H. M. ;

Lum, A. ;

Jones, S. ;

Senz, J. ;

Seckin, T. ;

Ho, J. ;

Wu, R. -C. ;

Lac, V. ;

Ogawa, H. ;

Tessier-Cloutier, B. ;

Alhassan, R. ;

Wang, A. ;

Wang, Y. ;

Cohen, J. D. ;

Wong, F. ;

Hasanovic, A. ;

Orr, N. ;

Zhang, M. ;

Popoli, M. ;

McMahon, W. ;

Wood, L. D. ;

Mattox, A. ;

Allaire, C. ;

Segars, J. ;

Williams, C. ;

Tomasetti, C. ;

Boyd, N. ;

Kinzler, K. W. ;

Gilks, C. B. ;

Diaz, L. ;

Wang, T. -L. ;

Vogelstein, B. ;

Yong, P. J. ;

Huntsman, D. G. ;

Shih, I. -M. .

NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (19) :1835-1848

[5] Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma [J].

Ayturk, Ugur M. ;

Couto, Javier A. ;

Hann, Steven ;

Mulliken, John B. ;

Williams, Kaitlin L. ;

Huang, August Yue ;

Fishman, Steven J. ;

Boyd, Theonia K. ;

Kozakewich, Harry P. W. ;

Bischoff, Joyce ;

Greene, Arin K. ;

Warman, Matthew L. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2016, 98 (04) :789-795

[6] Notch as a hub for signaling in angiogenesis [J].

Benedito, Rui ;

Hellstrom, Mats .

EXPERIMENTAL CELL RESEARCH, 2013, 319 (09) :1281-1288

[7] The epidemiology of brain arteriovenous malformations [J].

Berman, MF ;

Sciacca, RR ;

Pile-Spellman, J ;

Stapf, C ;

Connolly, ES ;

Mohr, JP ;

Young, WL .

NEUROSURGERY, 2000, 47 (02) :389-+

[8]

Boscolo E, 2006, INT J MOL MED, V18, P813

[9] Incidence and prevalence of intracranial vascular malformations in Olmsted County, Minnesota, 1965 to 1992 [J].

Brown, RD ;

Wiebers, DO ;

Torner, JC ;

OFallon, WN .

NEUROLOGY, 1996, 46 (04) :949-952

[10] Oncogenic KRAS and BRAF activation of the MEK/ERK signaling pathway promotes expression of dual-specificity phosphatase 4 (DUSP4/MKP2) resulting in nuclear ERK1/2 inhibition [J].

Cagnol, S. ;

Rivard, N. .

ONCOGENE, 2013, 32 (05) :564-576

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