KRAS G12D or G12V Mutation in Human Brain Arteriovenous Malformations

Oka, Mieko; Kushamae, Mika; Aoki, Tomohiro; Yamaguchi, Tadashi; Kitazato, Keiko T.; Abekura, Yu; Kawamata, Takakazu; Mizutani, Tohru; Miyamoto, Susumu; Takagi, Yasushi

doi:10.1016/j.wneu.2019.03.105

Cited by 41 publications

(47 citation statements)

References 25 publications

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“…Of note, a recent immunohistochemistry study demonstrated that KRAS G12D tended to be expressed in ECs of dilated vessels in bAVMs. 4 This matches our observation in zebrafish and mouse models that active KRAS-expressing vessels feature a distinctly large diameter. The mechanisms responsible for the expanded lumen are not yet clear, but we provide evidence that active KRAS signaling leads to enhanced EC size.…”

Section: Discussionsupporting

confidence: 88%

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Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Fish

Flores-Suarez

Boudreau

et al. 2020

Circulation Research

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Rationale: We previously identified somatic activating mutations in the KRAS gene in the endothelium of the majority of human sporadic brain arteriovenous malformations (bAVMs); a disorder characterized by direct connections between arteries and veins. However, whether this genetic abnormality alone is sufficient for lesion formation, as well as how active KRAS signaling contributes to AVM formation, remains unknown. Objective: To establish the first in vivo models of somatic KRAS gain of function in the endothelium in both mice and zebrafish in order to directly observe the phenotypic consequences of constitutive KRAS activity at a cellular level in vivo, and to test potential therapeutic interventions for AVMs. Methods and Results: Using both postnatal and adult mice, as well as embryonic zebrafish, we demonstrate that endothelial-specific gain of function mutations in Kras (G12D or G12V) are sufficient to induce bAVMs. Active KRAS signaling leads to altered endothelial cell morphogenesis and increased cell size, ectopic sprouting, expanded vessel lumen diameter, and direct connections between arteries and veins. Furthermore, we show that these lesions are not associated with altered endothelial growth dynamics or a lack of proper arteriovenous identity, but instead appear to feature exuberant angiogenic signaling. Finally, we demonstrate that KRAS-dependent AVMs in zebrafish are refractory to inhibition of the downstream effector PI3K, but instead require active MEK signaling. Conclusions: We demonstrate that active KRAS expression in the endothelium is sufficient for bAVM formation, even in the setting of uninjured adult vasculature. Furthermore, the finding that KRAS-dependent lesions are reversible in zebrafish suggests that MEK inhibition may represent a promising therapeutic treatment for AVM patients.

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Section: Discussionsupporting

confidence: 88%

“… 3 This finding of somatic KRAS mutations has since been confirmed by others. 4 – 7 However, no preclinical studies have been performed to test whether active KRAS mutations are sufficient to drive the formation of arteriovenous malformations (AVMs).…”

mentioning

confidence: 99%

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Fish

Flores-Suarez

Boudreau

et al. 2020

Circulation Research

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“…10 The presence of activating KRAS mutations in more than half of bAVM tissue samples may indicate the pathogenic role of these KRAS mutations. 78 In sporadic bAVMs, KRAS mutations were also detected in 9 of 15 specimens (60%), and seven of them were G12V or G12D mutations. 79 Priemer et al demonstrated the first reported instance of a KRAS p.G12C mutation in a bAVM.…”

Section: Krasmentioning

confidence: 95%

Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications

Ota

Komiyama

2020

Interv Neuroradiol

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Brain arteriovenous malformations have a high risk of intracranial hemorrhage, which is a substantial cause of morbidity and mortality in patients with brain arteriovenous malformations. Although a variety of genetic factors leading to hereditary brain arteriovenous malformations have been extensively investigated, their pathogenesis is still not well elucidated, especially in sporadic brain arteriovenous malformations. The authors have reviewed the updated data of not only the genetic aspects of sporadic brain arteriovenous malformations, but also the architecture of microvasculature, the roles of the angiogenic factors, and the signaling pathways. This knowledge may allow us to infer the pathogenesis of sporadic brain arteriovenous malformations and develop pre-emptive treatments for them.

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“…Not listed [28] PIK3CA inhibitors such as alpelisib [26] Breast cancer PI3K-AKT-mTOR pathway activation ALK TPM3-ALK, TPM4-ALK Inflammatory myofibroblastic tumor ∼ 50% [29] ALK inhibitors [30] such as alectinib [31] Non-small cell lung cancer ALK pathway activation [32] NOTCH1 Loci not specified Aging esophagus 12-80% [33] No specific inhibitors approved Colon cancer Wnt-betacatenin pathway activation [34] KRAS G12V or G12D Arteriovenous malformations in brain ∼ 63% [35,36] MEK inhibitors such as trametinib [16] Colorectal and pancreatic cancer RAS-RAF-MEK-ERK pathway upregulation [15] G12C, G12V, G12A, G12D, G12R…”

Section: H1047l H1047rmentioning

confidence: 99%

“…With the advances in next-generation sequencing (NGS) and the resulting identification of driver mutations for various cancers, there has been growing interest in the phenomenon in which well-known cancer-causing genes are altered in benign conditions, some of which have either no (or very limited) potential for malignant transformation (Table 1): (i) FGFR3 activating mutations are well documented to play a major role in the pathogenesis of bladder cancer [124][125][126], yet they are also found in unrelated conditions such as seborrheic keratosis and epidermal nevi [19][20][21][22]; (ii) mutations in the TP53 tumor suppressor gene, which are perhaps the most common alterations in cancer [140], also characterize the synovium of rheumatoid arthritis [37,38]; (iii) KRAS mutations are found in arteriovenous malformations [35,36,141] and in endometriosis [27] (though their functional role is still unclear in these conditions); and (iv) brain somatic mutations in Alzheimer's disease, in which about 27% of patients (14 of 52) have alterations in genes of the PI3K-AKT, MAPK, and AMPK pathways, are known to contribute to hyper-phosphorylation of tau [47]. Importantly, some of the loci that are mutated in each of these cases do not differ from the loci that are mutated and implicated in cancer.…”

Section: Sporadic Benign Conditions Associated With Alterations In "Dmentioning

confidence: 99%

The paradox of cancer genes in non-malignant conditions: implications for precision medicine

et al. 2020

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Next-generation sequencing has enabled patient selection for targeted drugs, some of which have shown remarkable efficacy in cancers that have the cognate molecular signatures. Intriguingly, rapidly emerging data indicate that altered genes representing oncogenic drivers can also be found in sporadic non-malignant conditions, some of which have negligible and/or low potential for transformation to cancer. For instance, activating KRAS mutations are discerned in endometriosis and in brain arteriovenous malformations, inactivating TP53 tumor suppressor mutations in rheumatoid arthritis synovium, and AKT, MAPK, and AMPK pathway gene alterations in the brains of Alzheimer's disease patients. Furthermore, these types of alterations may also characterize hereditary conditions that result in diverse disabilities and that are associated with a range of lifetime susceptibility to the development of cancer, varying from near universal to no elevated risk. Very recently, the repurposing of targeted cancer drugs for non-malignant conditions that are associated with these genomic alterations has yielded therapeutic successes. For instance, the phenotypic manifestations of CLOVES syndrome, which is characterized by tissue overgrowth and complex vascular anomalies that result from the activation of PIK3CA mutations, can be ameliorated by the PIK3CA inhibitor alpelisib, which was developed and approved for breast cancer. In this review, we discuss the profound implications of finding molecular alterations in non-malignant conditions that are indistinguishable from those driving cancers, with respect to our understanding of the genomic basis of medicine, the potential confounding effects in early cancer detection that relies on sensitive blood tests for oncogenic mutations, and the possibility of reverse repurposing drugs that are used in oncology in order to ameliorate nonmalignant illnesses and/or to prevent the emergence of cancer.

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KRAS G12D or G12V Mutation in Human Brain Arteriovenous Malformations

Cited by 41 publications

References 25 publications

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling

Pathogenesis of non-hereditary brain arteriovenous malformation and therapeutic implications

The paradox of cancer genes in non-malignant conditions: implications for precision medicine

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