ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor

Li, Dong; March, Michael; Gutiérrez-Uzquiza, Álvaro; Kao, Charlly; Seiler, Christoph; Pinto, Erin; Matsuoka, Leticia S.; Battig, Mark R.; Bhoj, Elizabeth; Wenger, Tara L.; Tian, Lifeng; Robinson, Nora; Wang, Tiancheng; Liu, Yichuan; Weinstein, Brant M.; Swift, Matthew; Jung, Hyun Min; Kaminski, Courtney N; Chiavacci, Rosetta M.; Perkins, Jonathan A.; Levine, Michael A.; Sleiman, Patrick; Hicks, Patricia J.; Strausbaugh, Janet T.; Belasco, Jean B.; Dori, Yoav; Hákonarson, Hákon

doi:10.1038/s41591-019-0479-2

Cited by 176 publications

(190 citation statements)

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“…Recent information also indirectly suggests that RAS pathway inhibition might be useful for the treatment of lymphovascular abnormalities in NS. Two patients with central conducting lymphatic anomaly (CCLA) were observed to have the same gain‐of‐function de novo Ser214Pro allele in ARAF (Li, D et al, ). This allele altered the same amino acid residue as observed in pathogenic RAF1 variants underlying NS.…”

Section: Future Prospects For Treating Ns‐related Chdmentioning

confidence: 99%

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Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Linglart

Gelb

2020

American J of Med Genetics Pt C

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Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left‐sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen‐activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype–phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome‐specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.

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Section: Future Prospects For Treating Ns‐related Chdmentioning

confidence: 99%

“…Pretreatment, the patient presents distinct dilation and beading of the lymphatic system; after a 12‐month treatment, the patient displays resorption of the dilated ducts and formation of new and symmetrical lymphatic networks. Figure reprinted with permission from Springer Nature (Li, D et al, )…”

Section: Future Prospects For Treating Ns‐related Chdmentioning

confidence: 99%

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Linglart

Gelb

2020

American J of Med Genetics Pt C

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“…In sporadic cancer, RAS isoforms are somatically mutated at three main hotspots (Gly 12 , Gly 13 , and Gln 61 ); these variants render RAS GAPinsensitive, and thus persistently GTP-bound and active (Cox et al, 2014;Cox & Der, 2002 F I G U R E 1 RASopathy-associated genes are components of the Ras/MAPK pathway. In this figure, RAS GEF corresponds to SOS1 or SOS2, RAS GAP corresponds to NF1, RASA1, RASA2 or SYNGAP1, RAS corresponds to HRAS, NRAS, KRAS, RRAS, MRAS or RIT1, and RAF corresponds to ARAF, BRAF, or RAF1) have been found in lung adenocarcinoma and melanoma but have yet to be found in individuals with classical RASopathies; however, this variant has been associated with lymphatic anomaly (Li et al, 2019).…”

Section: Defining the Art Rasopathy Genes: The Genes Of The Ras/mapmentioning

confidence: 99%

“…This hotspot mutation allows for the BRAF kinase to be active in the absence of dimerization and in the absence of active RAS (Freeman, Ritt, & Morrison, ). The Class I, BRAF Val 600 , variants are uncommon in RASopathies (Li et al, ), but non‐Val 600 Class II and Class III BRAF variants are observed in CFC. Class II BRAF variants function as RAS‐independent constitutively active dimers, while Class III BRAF variants increase MAPK signaling due to an increased ability to be activated by RAS (Dankner, Rose, Rajkumar, Siegel, & Watson, ).…”

Section: Introductionmentioning

confidence: 99%

“…The RAF family member RAF1 is rarely mutated in cancer, but germline pathogenic variants in RAF1 are found in individuals with NS (Pandit et al, ). Somatic variants in ARAF at the Ser 214 codon have been found in lung adenocarcinoma and melanoma but have yet to be found in individuals with classical RASopathies; however, this variant has been associated with lymphatic anomaly (Li et al, ). Germline and somatic variants in ARAF and RAF1 primarily prevent these kinases from being inhibited through their interactions with 14‐3‐3 proteins (Molzan et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

Gross

Frone

Gripp

et al. 2020

American J of Med Genetics Pt A

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RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.

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Barriers to Genetic Testing in Vascular Malformations

et al. 2023

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ImportanceVascular malformations (VMs) are rare disorders of vasculogenesis associated with substantial morbidity. Improved understanding of their genetic basis is increasingly guiding management, but logistical barriers to obtaining genetic testing in patients with VM may constrain treatment options.ObjectivesTo examine the institutional mechanisms for and obstacles to obtaining genetic testing for VM.Design, Setting, and ParticipantsThis survey study invited members of the Pediatric Hematology-Oncology Vascular Anomalies Interest Group, representing 81 vascular anomaly centers (VACs) serving individuals up to 18 years of age, to complete an electronic survey. Respondents were mostly pediatric hematologists-oncologists (PHOs) but included geneticists, genetic counselors, clinic administrators, and nurse practitioners. Responses that were received between March 1 and September 30, 2022, were analyzed with descriptive methods. Requirements for genetic testing by several genetics laboratories were also reviewed. Results were stratified by size of the VAC.Main Outcomes and MeasuresVascular anomaly center and associated clinician characteristics and practice patterns for ordering and obtaining insurance approval for genetic testing for VMs were collected.ResultsResponses were received from 55 of 81 clinicians, for a response rate of 67.9%. Most respondents were PHOs (50 [90.9%]). Most respondents (32 of 55 respondents [58.2%]) replied that they order genetic testing on 5 to 50 patients per year and reported a genetic testing volume increase of 2- to 10-fold over the past 3 years (38 of 53 respondents [71.7%]). Most testing was ordered by PHOs (35 of 53 respondents [66.0%]), followed by geneticists (28 [52.8%]) and genetic counselors (24 [45.3%]). In-house clinical testing was more common at large and medium-sized VACs. Small VACs were more likely to use oncology-based platforms, which potentially miss low-frequency allelic variants in VM. Logistics and barriers varied by size of the VAC. Obtaining prior authorization was the duty shared among PHOs, nurses, and administrative staff, but the burden of insurance denials and appeals were on PHOs (35 of 53 respondents [66.0%]). Lack of administrative support; unclear institutional, insurance, and laboratory requirements; and lack of clinician education were barriers to genetic testing at VACs of all sizes. The effort to obtain genetic testing for patients with VM, compared with patients with cancer, was perceived as excessive, despite genetic testing being considered standard of care for this population.Conclusions and RelevanceResults of this survey study showed the barriers to genetic testing for VM across VACs, described differences between VACs based on size, and proposed multiple interventions to support clinicians ordering genetic testing for VM. The results and recommendations should have broader application to clinicians caring for patients for whom molecular diagnosis is important to medical management.

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ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor

Cited by 176 publications

References 45 publications

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

Barriers to Genetic Testing in Vascular Malformations

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