<i>RAS</i>and<i>RAF</i>mutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis

Dadzie, Ophelia E.; Yang, Shi; Emley, Andrew; Keady, Michelle; Bhawan, Jag; Mahalingam, Meera

doi:10.1111/j.1365-2133.2008.08887.x

Cited by 41 publications

(40 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…21 It has been previously pointed out that although activating mutations coexist, they are mutually exclusive at the single-cell level. 22 In the current study, intratumoral heterogeneity was seen only in one case, whereas intertumoral heterogeneity in the same patient (comparison of immunohistochemistry for NRAS mutational status of primary vs paired metastatic samples) was not an aim of the current study and future investigations will assess concordance of NRAS protein expression in multiple patient's tumors. Previous immunohistochemical analyses using BRAFV600E antibody have shown that intratumoral heterogeneity of BRAF mutation is not generally observed [23][24][25] and up to 100% concordance between matched primary and metastatic melanomas has been reported.…”

Section: Discussionmentioning

confidence: 71%

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

View full text Add to dashboard Cite

Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.

show abstract

Section: Discussionmentioning

confidence: 71%

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

View full text Add to dashboard Cite

show abstract

“…11 Our own previous experience has shown that the frequency could be even lower. 8 In spite of the low incidence rate, findings from this preliminary study shed light on the potential use of immunohistochemistry with the anti-B-Raf (V600E) antibody as an ancillary screening tool to assess the BRAFV600E mutation status in primary cutaneous melanoma. Further, in support of the specificity of this antibody, two cases in our cohort possessed mutations other than V600E (case 2 had a glutamic acid to lysine substitution while case 8 had a glutamic acid to methionine substitution) and were negative by immunohistochemistry (Figure 2).…”

Section: Discussionmentioning

confidence: 93%

“…[1][2][3] The BRAFV600E mutation is seen at particularly high rates in primary and metastatic melanoma (20-70%), papillary thyroid carcinoma (40-70%), colorectal carcinoma (5-10%), and in select benign tumors such as melanocytic nevi. 2,[4][5][6][7][8][9][10] Given its prevalence and role in increasing tumor cell proliferation and metastases, BRAFV600E has emerged as an important biomarker for clinicians. In early melanomas, the BRAF mutation status has not been shown to affect overall survival; however, in metastatic melanoma, it has been associated with a poorer survival rate.…”

mentioning

confidence: 99%

Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

2013

View full text Add to dashboard Cite

The V600E mutation of BRAF has emerged as both an effective biomarker and therapeutic target for select benign and malignant cutaneous and non-cutaneous human tumors and is typically determined using DNAbased techniques that include allele-specific PCR and direct DNA sequencing. Recently however, the development of new antibodies directed against the V600E protein has opened the door for an easier and more efficient strategy for identifying this mutation. Our present aim was to determine the efficacy of one such antibody, anti-B-Raf (V600E), a mouse monoclonal antibody in which the immunogen is a synthetic peptide derived from the internal region of BRAFV600E. A total of 35 cases of primary cutaneous melanoma were evaluated using a combination of DNA-based techniques that included allele-specific PCR and/or direct DNA sequencing and immunohistochemistry. Cases of papillary thyroid carcinomas (n ¼ 5) and colorectal carcinomas (n ¼ 5), known to harbor the BRAFV600E mutation, served as positive controls for the study. DNA analyses revealed that 6 of 35 (17%) cases of the primary cutaneous malignant melanoma possessed the BRAFV600E mutation. For immunohistochemical analyses, cytoplasmic positivity with anti-B-Raf was noted in 7 of 35 (20%) cases of primary melanoma and in all 10 positive controls. Statistical analyses of the data demonstrated that the sensitivity of the immunohistochemistry was 100% and specificity was 97%. Findings from the current study support the potential use of immunohistochemistry as an ancillary screening tool to assess the BRAFV600E mutation status in primary cutaneous melanoma.

show abstract

“…It is widely believed that a substantial percentage of melanomas arise from melanocytic nevi (Mooi and Krausz 2007). Indeed, several groups have provided genetic evidence that supports a progression model (Demunter et al 2001;Bogdan et al 2003;Yazdi et al 2003;Dadzie et al 2009). From the model outlined above, we and others deduced previously that abrogation of OIS of nevus cells may act as a rate-limiting event for melanomagenesis (Bennett 2003;Mooi and Peeper 2006).…”

mentioning

confidence: 99%

Abrogation of BRAF^V600E-induced senescence by PI3K pathway activation contributes to melanomagenesis

Vredeveld

Possik²,

Smit³

et al. 2012

Genes Dev.

246

247

View full text Add to dashboard Cite

Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear. We show here that PTEN depletion abrogates BRAF V600E -induced senescence in human fibroblasts and melanocytes. Correspondingly, in established murine BRAF V600E -driven nevi, acute shRNA-mediated depletion of PTEN prompted tumor progression. Furthermore, genetic analysis of laser-guided microdissected human contiguous nevus-melanoma specimens recurrently revealed identical mutations in BRAF or NRAS in adjacent benign and malignant melanocytes. The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15INK4B . This treatment also eliminated subpopulations resistant to targeted BRAF V600E inhibition. Our findings suggest that a significant proportion of melanomas arise from nevi. Furthermore, these results demonstrate that PI3K pathway activation serves as a rate-limiting event in this setting, acting at least in part by abrogating OIS. The reactivation of senescence features and elimination of cells refractory to BRAF V600E inhibition by PI3K inhibition warrants further investigation into the therapeutic potential of simultaneously targeting these pathways in melanoma.

show abstract

RASandRAFmutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis

Abstract: Our findings hint towards the interpretation of banal melanocytic aggregates serving as precursor lesions.

Cited by 41 publications

References 31 publications

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

Abrogation of BRAF^V600E-induced senescence by PI3K pathway activation contributes to melanomagenesis

Contact Info

Product

Resources

About

RASandRAFmutations in banal melanocytic aggregates contiguous with primary cutaneous melanoma: clues to melanomagenesis

Abstract: Our findings hint towards the interpretation of banal melanocytic aggregates serving as precursor lesions.

Cited by 41 publications

References 31 publications

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis

Contact Info

Product

Resources

About

Abrogation of BRAF^V600E-induced senescence by PI3K pathway activation contributes to melanomagenesis