RASopathy Gene Mutations in Melanoma

Halaban, Ruth; Krauthammer, Michael

doi:10.1016/j.jid.2016.05.095

Cited by 29 publications

(27 citation statements)

References 41 publications

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“…Interestingly, NF1 loss in melanoma is often associated with concurrent mutations in RASopathy genes 90,102 . These include RAS p21 protein activator 2 ( RASA2 ), PTPN11 , SOS1 , RAF1 , and SPRED1 , mutated in the germline of individuals with Noonan syndrome ( RASA2 , PTPN11 , SOS1 , RAF1 ), Noonan syndrome with multiple lentigines ( PTPN11 , RAF1 ), and Legius syndrome ( SPRED1 ) (Figure 1).…”

Section: Nf1 Mutations In Melanomamentioning

confidence: 99%

“…These include RAS p21 protein activator 2 ( RASA2 ), PTPN11 , SOS1 , RAF1 , and SPRED1 , mutated in the germline of individuals with Noonan syndrome ( RASA2 , PTPN11 , SOS1 , RAF1 ), Noonan syndrome with multiple lentigines ( PTPN11 , RAF1 ), and Legius syndrome ( SPRED1 ) (Figure 1). It is suggested that the co-occurring mutations may act synergistically in melanomas 102 .…”

Section: Nf1 Mutations In Melanomamentioning

confidence: 99%

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The NF1 gene in tumor syndromes and melanoma

Kiuru

Busam

2017

Laboratory Investigation

157

133

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Activation of the RAS/MAPK pathway is critical in melanoma. Melanoma can be grouped into four molecular subtypes based on their main genetic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, and triple wild-type tumors. The NF1 protein, neurofibromin 1, negatively regulates RAS proteins through GTPase activity. Germline mutations in NF1 cause neurofibromatosis type I, a common genetic tumor syndrome caused by dysregulation of the RAS/MAPK pathway, i.e. RASopathy. Melanomas with NF1 mutations typically occur on chronically sun-exposed skin or in older individuals, show a high mutation burden, and are wild-type for BRAF and NRAS. Additionally, NF1 mutations characterize certain clinicopathologic melanoma subtypes, specifically desmoplastic melanoma. This review discusses the current knowledge of the NF1 gene and neurofibromin 1 in neurofibromatosis type I and in melanoma.

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Section: Nf1 Mutations In Melanomamentioning

confidence: 99%

Section: Nf1 Mutations In Melanomamentioning

confidence: 99%

The NF1 gene in tumor syndromes and melanoma

Kiuru

Busam

2017

Laboratory Investigation

157

133

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“…As an example, patients with "RASopathies" (a group of rare genetic conditions such as cardiofaciocutaneous syndrome and Costello syndrome caused by mutations in genes of the RAS-RAF-MAPK pathway) have an increased risk of juvenile myelomonocytic leukemia, brain tumors, acute lymphoblastic leukemia, rhabdomyosarcoma, and neuroblastoma [55]. These patients do not, however, have increased risk of classic BRAF-mutated melanoma, although~75% of the cardiofaciocutaneous syndromes result from germline BRAF mutations [162], and pigmented nevi are very distinct in this syndrome and help to define it [163].…”

Section: Hereditary Conditions That Results From Germline Cancer-relatmentioning

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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“…The fetus was found to have a missense variant, c.622A>G (p.Ile208Val), in BRAF . Somatic variants in BRAF are well-documented in various cancers (Holderfield et al 2014; Halaban and Krauthammer 2016) and germline variants have been reported in individuals with RASopathies. Of note, at least nine BRAF missense variants have been observed in patients with Noonan syndrome, five of them de novo occurrences (Razzaque et al 2007; Nystrom et al 2008; Sarkozy et al 2009; Lee et al 2011; van Trier et al 2016).…”

Section: Case Presentationsmentioning

confidence: 99%

Reclassification of the BRAF p.Ile208Val variant by case-level data sharing

Grant

Hemphill

Vincent³

et al. 2018

Cold Spring Harb Mol Case Stud

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The ClinVar database is a useful tool for patients and physicians to view variant interpretations submitted by clinical and nonclinical labs. However, variants of uncertain significance (VUS) in ClinVar can pose a significant burden on patients. If possible, it is important to resolve discrepancies and uncertainties surrounding interpreted variants. Here we highlight a case of a family who received a report of a variant (c.622A>G, p.Ile208Val) in BRAF following prenatal RASopathy testing. The variant had been previously classified by our laboratory as a VUS, so the mother contacted our laboratory via ClinVar for further information, which prompted reevaluation of the variant. Multiple sources of case-level data as well as the presence of the variant in the general population yielded sufficient evidence to reclassify the variant as likely benign. This reclassification alleviated significant concern for the family, and the child was born healthy with no clinical manifestations of Noonan syndrome or a RASopathy.

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RASopathy Gene Mutations in Melanoma

Cited by 29 publications

References 41 publications

The NF1 gene in tumor syndromes and melanoma

The NF1 gene in tumor syndromes and melanoma

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

Reclassification of the BRAF p.Ile208Val variant by case-level data sharing

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