BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients

Malapelle, Umberto; Rossi, Giulio; Pisapia, Pasquale; Barberis, Massimo; Buttitta, Fiamma; Castiglione, Francesca; Cecere, Fabiana Letizia; Grimaldi, Antonio; Iaccarino, Antonino; Marchetti, Antonio; Massi, Daniela; Medicina, Daniela; Mele, Fabio; Minari, Roberta; Orlando, Elisabetta; Pagni, Fabio; Palmieri, Giuseppe; Righi, Luisella; Russo, Alessandro; Tommasi, Stefania; Vermi, William; Troncone, Giancarlo

doi:10.1016/j.critrevonc.2020.103118

Cited by 24 publications

(18 citation statements)

References 153 publications

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“…Moreover, observational studies have described the association between MSI and KRAS mutation as the hallmark of a worse prognosis of mucinous CRC with metastatic profile [ 41 , 42 ]. Thus, wild type or mutated KRAS always in association with microsatellite stability, is a negative predictor for disease survival [ 43 , 44 ]. Besides, the presence of hereditary settings in MSI can be linked to KRAS mutations or to the Lynch syndrome.…”

Section: Discussionmentioning

confidence: 99%

Concomitant Mutations G12D and G13D on the Exon 2 of the KRAS Gene: Two Cases of Women with Colon Adenocarcinoma

et al. 2021

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Colorectal cancer (CRC) is rapidly increasing representing the second most frequent cause of cancer-related deaths. From a clinical-molecular standpoint the therapeutically management of CRC focuses on main alterations found in the RAS family protein, where single mutations of KRAS are considered both the hallmark and the target of this tumor. Double and concomitant alterations of KRAS are still far to be interpreted as molecular characteristics which could potentially address different and more personalized treatments for patients. Here, we firstly describe the case of two patients at different stages (pT2N0M0 and pT4cN1cM1) but similarly showing a double concurrent mutations G12D and G13D in the exon 2 of the KRAS gene, normally mutually exclusive. We also evaluated genetic testing of dihydropyrimidine dehydrogenase (DPYD) and microsatellite instability (MSI) by real-time PCR and additional molecular mutations by next generation sequencing (NGS) which resulted coherently to the progression of the disease. Accordingly, we reinterpreted and discuss the clinical history of both cases treated as single mutations of KRAS but similarly progressing towards a metastatic asset. We concluded that double mutations of KRAS cannot be interpreted as univocal genomic alterations and that they could severely impact the clinical outcome in CRC, requiring a tighter monitoring of patients throughout the time.

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Section: Discussionmentioning

confidence: 99%

Concomitant Mutations G12D and G13D on the Exon 2 of the KRAS Gene: Two Cases of Women with Colon Adenocarcinoma

et al. 2021

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“…1,2 However, although its incidence continues to increase, mortality rates have significantly declined with the advent of immune checkpoint inhibitors (ICIs) and targeted therapies. [3][4][5][6] Accordingly, pathologists are now strongly encouraged to identify and report the presence of specific gene mutations in metastatic melanoma patients for whom targeted therapies are available. 7 Generally, the most common gene alteration in melanoma is V-Raf Murine Sarcoma Viral Oncogene Homologue B (BRAF), which is present in about 40%-60% of all cases.…”

Section: Introductionmentioning

confidence: 99%

“…Cutaneous melanoma is an aggressive neoplasm, accounting for about 1.7% of all novel cancer diagnoses and 0.6% of all cancer‐related deaths worldwide 1,2 . However, although its incidence continues to increase, mortality rates have significantly declined with the advent of immune checkpoint inhibitors (ICIs) and targeted therapies 3–6 . Accordingly, pathologists are now strongly encouraged to identify and report the presence of specific gene mutations in metastatic melanoma patients for whom targeted therapies are available 7 …”

Section: Introductionmentioning

confidence: 99%

Multiple predictive biomarker testing in melanoma: Another challenge in identifying the optimal approach on cytological samples

et al. 2023

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Background:The management of cutaneous melanoma has changed dramatically in recent years thanks to the development of tyrosine kinase and immune-checkpoint inhibitors (ICIs). Thus, multiple biomarker testing is becoming ever more important for the identification of patients who are potentially eligible for these treatments. One reliable approach to the molecular evaluation of metastatic melanoma is fine needle cytology (FNC). To examine the utility of this approach for assessing PD-L1 expression levels, we evaluated the cellular adequacy of residual cell block (CB) material from metastatic melanomas that were previously tested for BRAF and NRAS mutations. Methods:We retrieved from our internal archives a series of FNC samples of metastatic melanoma that had been subjected to molecular testing on residual CB material or a dedicated needle rinse between January 2016 and July 2022. Real-time polymerase chain reaction was used to assess BRAF and NRAS status, and an SP263 assay was employed to ascertain PD-L1 expression levels.Results: Overall, n = 19 cases were selected. Of these, 11 (57.9%) cases revealed a BRAF exon 15 p.V600E mutation, one case (5.3%) revealed NRAS mutation, and seven cases (36.8%) showed no mutations. Regarding PD-L1 assessment, 16/19 (84.2%) cases were deemed adequate, meaning they contained at least 100 viable cells. Conclusions:We highlighted the feasibility of assessing PD-L1 expression levels in residual CB material from metastatic melanomas previously tested for BRAF and NRAS mutations. Moreover, we pointed out that FNC needle rinses may be an alternative source of nucleic acids for molecular testing, preserving CB material for immunocytochemistry evaluation.

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“…However, they can only be used to determine a limited range of mutations and are not always specific to the mutation type. Sequencing-based methods allow the detection and differentiation of the already known and new mutations [ 12 - 14 ]. Pyrosequencing is superior to Sanger sequencing in terms of sensitivity in the detection of a minor DNA fraction (about 15–20% for Sanger sequencing and 1–5% for pyrosequencing) [ 12 - 16 ].…”

Section: Introductionmentioning

confidence: 99%

A Complex of Pyrosequencing-Based Methods for Detection of Somatic Mutations in Codons 600 and 601 of the BRAF Gene

Dribnokhodova¹,

Esman²,

Korchagin³

et al. 2022

Sovrem Tehnol Med

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The aim of the study is to develop methods for the differentiation of mutations in the BRAF codon 600 and to increase the sensitivity of the K601E mutation detection.Materials and Methods. The nucleotide sequence of the BRAF codons 592-602 was identified using the PyroMark Q24 genetic analysis system. The mutations search in codon 600 was conducted using the 600-S primer in line with the following order of adding nucleotides: GCTGTCАTCTGCTAGCTAGAC (corresponding to nucleotides 1799-1786). The K601E mutation was detected using the 601-S primer in line with the following order of nucleotide addition: GCTACTCACTGTAG (corresponding to nucleotides 1801-1793). The analytical characteristics of the proposed methods for somatic mutations' detection were determined using dilutions of plasmid DNA samples containing the BRAF gene region without mutations or with one of the following mutations: V600E, V600R, V600K, V600M, and K601E. Validation was performed on 132 samples of biological material obtained from the thyroid nodules.Results. The developed methods allow to determine 2% of the V600E or V600M mutations, 1% of the V600K and V600R mutations, and 3% of the K601E mutations in samples with high DNA concentration; it is also possible to confidently detect at least 5% of the mutant allele for all mutations in low concentration samples (less than 500 copies/PCR). During biological material testing, 53 samples with the V600E mutation were detected; the proportion of the mutant allele was 4.9-50.0%. Conclusion.A complex of methods for determination of the nucleotide sequence of the BRAF codons 592-601 and the algorithm for testing samples and analyzing mutations in the BRAF codons 600-601 was developed. The method provides sufficient sensitivity to detect frequent mutations in codons 600 and 601 and allows them to be precisely differentiated.

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BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients

Cited by 24 publications

References 153 publications

Concomitant Mutations G12D and G13D on the Exon 2 of the KRAS Gene: Two Cases of Women with Colon Adenocarcinoma

Concomitant Mutations G12D and G13D on the Exon 2 of the KRAS Gene: Two Cases of Women with Colon Adenocarcinoma

Multiple predictive biomarker testing in melanoma: Another challenge in identifying the optimal approach on cytological samples

A Complex of Pyrosequencing-Based Methods for Detection of Somatic Mutations in Codons 600 and 601 of the BRAF Gene

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