BRAF,NRASandHRASmutations in spitzoid tumours and their possible pathogenetic significance

Forno, Philip Da; Fletcher, A.; Bamford, M.; Su, Lyndon D.; Potter, Linda; Saldanha, Gerald

doi:10.1111/j.1365-2133.2009.09181.x

Cited by 82 publications

(49 citation statements)

References 28 publications

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“…DNA sequencing for H-RAS analysis was performed as previously described. 29 A total of 5 L of purified cycle-sequencing product were then analyzed using an ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Milan, Italy).…”

Section: Braf V600e and H-ras Mutations Detectionmentioning

confidence: 99%

Atypical Spitzoid melanocytic tumors: A morphological, mutational, and FISH analysis

Massi

Cesinaro

Tomasini

et al. 2011

Journal of the American Academy of Dermatology

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Section: Braf V600e and H-ras Mutations Detectionmentioning

confidence: 99%

Atypical Spitzoid melanocytic tumors: A morphological, mutational, and FISH analysis

Massi

Cesinaro

Tomasini

et al. 2011

Journal of the American Academy of Dermatology

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“…15,[17][18][19][24][25][26][27] In addition, all published cases of HRAS-mutated Spitz tumors with clinical followup have behaved in a benign fashion, suggesting that the presence of a HRAS mutation in a lesion with Spitzoid morphology is a good prognostic indicator. [15][16][17] The presence of an activating HRAS mutation in 6% of deep penetrating nevi in our study sheds new light on the molecular pathogenesis of these tumors. As in both benign Spitz nevi with HRAS mutations, and BRAF mutations in a majority of benign melanocytic nevi, a RAS mutation is not sufficient to promote malignant change within a nevus.…”

Section: Discussionmentioning

confidence: 99%

“…For example, genetic analysis of Spitzoid melanocytic proliferations has revealed that approximately 15% of Spitz nevi harbor mutations in HRAS, typically in either exon 2 (codon 12 or 13) or exon 3 (codon 61). [15][16][17][18][19] This is in contrast to all spitzoid melanomas and conventional melanomas that have been analyzed to date, in which HRAS mutations are rare. 17,19,20 In addition, BRAF and NRAS mutations are uncommon in Spitz nevi, whereas they are common in melanomas.…”

mentioning

confidence: 99%

“…[15][16][17][18][19] This is in contrast to all spitzoid melanomas and conventional melanomas that have been analyzed to date, in which HRAS mutations are rare. 17,19,20 In addition, BRAF and NRAS mutations are uncommon in Spitz nevi, whereas they are common in melanomas. 21 Thus the presence of an HRAS mutation in a melanocytic neoplasm with Spitzoid morphology appears to favor the diagnosis of Spitz nevus, rather than a Spitzoid melanoma.…”

mentioning

confidence: 99%

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Identification of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi

Bender

McGinniss²,

Esmay

et al. 2013

Modern Pathology

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HRAS is mutated in B15% of Spitz nevi, and GNAQ or GNA11 is mutated in blue nevi (46-83% and B7% respectively). Epithelioid blue nevi and deep penetrating nevi show features of both blue nevi (intradermal location, pigmentation) and Spitz nevi (epithelioid morphology). Epithelioid blue nevi and deep penetrating nevi can also show overlapping features with melanoma, posing a diagnostic challenge. Although epithelioid blue nevi are considered blue nevic variants, no GNAQ or GNA11 mutations have been reported. Classification of deep penetrating nevi as blue nevic variants has also been proposed, however, no GNAQ or GNA11 mutations have been reported and none have been tested for HRAS mutations. To better characterize these tumors, we performed mutational analysis for GNAQ, GNA11, and HRAS, with blue nevi and Spitz nevi as controls. Within deep penetrating nevi, none demonstrated GNAQ or GNA11 mutations (0/38). However, 6% revealed HRAS mutation (2/32). Twenty percent of epithelioid blue nevi contained a GNAQ mutation (2/10), while none displayed GNA11 or HRAS mutation. Eighty-seven percent of blue nevi contained a GNAQ mutation (26/30), 4% a GNA11 mutation (1/28), and none an HRAS mutation. Within Spitz nevi, none demonstrated GNAQ or GNA11 mutations (0/30). Seventeen percent contained an HRAS mutation (5/30). All GNAQ and GNA11 mutations were p.Q209L (c.626A4T) point mutations, except 2 GNAQ mutations, which contained novel c.625_626CA4TT double mutations. Four HRAS mutations were in exon 2, and three in exon 3. This is the first study to identify HRAS mutations in deep penetrating nevi. The presence of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi suggests classification of these unusual nevi within the Spitz nevus category of melanocytic tumors, rather than the blue nevus category. Modern Pathology (2013) 26, 1320-1328; doi:10.1038/modpathol.2013.77; published online 19 April 2013 Keywords: blue nevus; deep penetrating nevus; epithelioid blue nevus; GNA11; GNAQ; HRAS; spitz nevus Melanocytic nevi with epithelioid cytomorphology include epithelioid and spindle cell (Spitz) nevi, epithelioid blue nevi, and deep penetrating nevi. Deep penetrating nevus, a term first coined by Seab et al, 1 are unusual melanocytic neoplasms difficult to classify. Deep penetrating nevi are uncommon but are of importance due to their histological and clinical overlap with melanoma. They most commonly present on the extremities, followed by the head and neck and upper trunk. 2 The age range at presentation is wide; however, as with Spitz nevi, deep penetrating nevi most commonly present in younger patients (adolescence and young adults). They typically present as predominantly dermal to focally compound melanocytic proliferations with extension into the reticular dermis particularly along adnexal structures and neurovascular bundles, often extending into the subcutis. They tend to have a relatively symmetric wedge-shaped nodular growth pattern, although superficial variants can occur. 2 A plexiform disp...

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“…66,[97][98][99][100] In particular, mutations in HRAS have been frequently detected in Spitz nevi. 101 Congenital nevi often harbor mutations in NRAS gene, 102,103 whereas acquired nevi are composed of melanocytes carrying BRAF mutations. 99 The same mutations in these genes were found in malignant melanomas albeit surprisingly at frequencies lower than that in benign nevi, 99,104,105 suggesting that malignant melanomas, which are frequently derived from nevi, have developed a mechanism(s) for suppressing OIS.…”

Section: Different Types Of Oismentioning

confidence: 99%

Controversial aspects of oncogene-induced senescence

Bianchi‐Smiraglia

Nikiforov

2012

Cell Cycle

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BRAF,NRASandHRASmutations in spitzoid tumours and their possible pathogenetic significance

Cited by 82 publications

References 28 publications

Atypical Spitzoid melanocytic tumors: A morphological, mutational, and FISH analysis

Atypical Spitzoid melanocytic tumors: A morphological, mutational, and FISH analysis

Identification of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi

Controversial aspects of oncogene-induced senescence

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