Low Frequency Of BRAF Mutations Research Articles

Optimal strategy in managing advanced melanoma.

The advent of immune checkpoint inhibitors and combination therapy with BRAF inhibitors and MEK inhibitors has dramatically improved the prognosis of advanced melanoma. However, since acral melanoma and mucosal melanoma, which are rare in Western countries but are major subtypes of melanoma in East Asia, including Japan, have a low frequency of BRAF mutations, there are currently no treatment options other than immune checkpoint inhibitors in most such cases. Furthermore, owing to a lower tumor mutation burden, immune checkpoint inhibitors are less effective in acral and mucosal melanoma than in cutaneous melanoma. The aim of this review was to summarize the current status and future prospects for the treatment of advanced melanoma, comparing cutaneous melanoma, acral melanoma, and mucosal melanoma.

Prevalence of colorectal cancer biomarkers and their impact on clinical outcomes in Riyadh, Saudi Arabia.

ObjectivesKRAS, NRAS, and BRAF mutations are commonly present in colorectal cancer (CRC). We estimated the frequency of KRAS, NRAS, and BRAF mutations and assessed their impact on survival and other clinical variables among Saudi patients.DesignRetrospective cohort study design.SettingsOncology department of a tertiary hospital in Riyadh, Saudi Arabia. We gathered information from 2016 to 2018.ParticipantsCohort of 248 CRC patients to assess the demographic data, pathological tumour features, response to treatment modalities, disease progression, and metastasis.Statistical analysis usedCorrelation analysis using the chi-square test. Survival analysis using a Kaplan Meier method. Cox regression analysis to calculate the hazard ratios.ResultsDemographic data revealed that 84% of patients were diagnosed with CRC above the age of 50 years. Only 27% of patients presented with distant metastasis. KRAS mutations were the most prevalent (49.6%), followed by NRAS mutations (2%) and BRAF mutations (0.4%). Wild type tumours were found among 44.4% of patients. KRAS mutation showed no significant correlation with the site, type, pathological grade, and stage of the tumour.The mean survival time was shorter among patients with KRAS mutations than among patients with wild type KRAS tumours (54.46 vs. 58.02 months). Adjusted analysis showed that the survival time was significantly affected by patients’ age at diagnosis (P = 0.04). Male patients had an increased risk of mortality by 77% (hazard ratio: 1.77).ConclusionsSaudi CRC patients had a high frequency of KRAS mutations and a low frequency of BRAF mutations. The KRAS mutation status did not affect the patients’ survival.

Unique clinicopathologic and genetic alteration features in early onset colorectal carcinoma compared with age-related colorectal carcinoma: a large cohort next generation sequence analysis

Colorectal carcinoma (CRC) is the third most common cancer type in the United States. While the incidence of CRC is decreasing among an older population undergoing screening, the incidence of early-onset CRC is rising. There is a growing understanding that the molecular underpinnings of colorectal carcinoma vary by age. In this study, we report the genetic alterations and clinicopathologic features of a single-institution colorectal carcinoma cohort over a 2-year period using a next-generation sequencing (NGS) approach and microsatellite stability (MS) status determined by immunohistochemical staining. Forty cases were identified in an early-onset colorectal carcinoma cohort (eCRC) defined by age <40 years, and 164 cases were identified in an age-related colorectal carcinoma cohort (arCRC) defined by age >70 years. eCRC was more often-left-sided/rectal and more likely to present high rates of lymph node positivity with metastatic disease. NGS mutational analysis revealed distinct differences between eCRC and arCRC, with eCRC being characterized by low frequency of PIK3CA mutations, elevated frequency of KRAS and CTNNB1 mutations in microsatellite instability high tumors, and very low frequency of BRAF mutations.

A gene is known by the company it keeps: enrichment of TNFAIP3 gene aberrations in MALT lymphomas expressing IGHV4-34 antigen receptors.

Associations between immunoglobulin (IG) receptors with distinctive immunogenetic features and particular gene mutations are a recurring theme in mature B-cell lymphomas. Relevant observations have been made in chronic lymphocytic leukemia (CLL), where gene mutations are distributed asymmetrically in cases bearing or not somatic hypermutations within the clonotypic immunoglobulin heavy chain variable region (IGHV) genes (e.g. TP53 mutations predominate in IG-unmutated CLL, whereas the opposite is seen for MYD88 mutations, enriched in IG-mutated CLL) and in subsets of cases with stereotyped IG (enrichment for SF3B1 mutations in CLL subset #2). Moreover, similar findings have been reported in splenic marginal-zone lymphoma, where KLF2 mutations are biased to cases expressing IGHV1-2*04 IG receptors, and in hairy cell leukemia, where IGHV4-34-expressing cases display a low frequency of BRAF mutations but a high frequency of MAP2K1 mutations. The list is now growing with the report of increased frequency of inactivating mutations in the TNFAIP3 gene in MALT lymphomas expressing IG receptors encoded by the IGHV4-34 gene, particularly of the ocular adnexa. Considering that TNFAIP3 encodes a negative regulator of NF-κB, this finding further highlights the importance of NF-κB pathway activation in the natural history of MALT lymphomas. Altogether, these findings allude to selection of genomic aberrations in lymphoma cases with distinctive immune signaling profiles linked to the expression of particular IG receptors. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease.

Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype. To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases. Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue. We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations. When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.

BRAF mutations in cutaneous melanoma: no correlation with histological prognostic factors or overall survival

INTRODUCTION: Molecular biology techniques allow identification of molecular markers such as BRAF and c-Kit gene mutations in melanomas. Studies on genetic alterations in melanomas of South-American patients are sparse. OBJECTIVES: To identify the incidence of BRAF and c-Kit gene mutations in primary cutaneous melanomas in Brazilian patients and to evaluate pathogenetic and prognostic implications of these mutations correlating them with clinical and histopathological data. MATERIAL AND METHODS: Ninety-six surgical specimens of primary cutaneous melanoma and 15 corresponding metastasis were analyzed using TaqMan Real-Time polymerase chain reaction (PCR) assays. RESULTS: In comparison with the medical literature, a relatively low frequency of BRAF mutation in primary (39%) and metastatic (40%) melanomas and complete absence of c-Kit gene mutations were demonstrated. BRAF mutations arose at an early stage during melanoma progression and were not involved in the transition of thin (< 1 mm) to thick (> 1 mm) melanomas. BRAF mutations are related to patients' younger age and to the pattern of sun exposure, although there was no correlation with any histological prognostic factor or overall survival. CONCLUSION: The identification of both BRAF and c-Kit mutation is not a suitable prognostic indicator in the Brazilian population. Moreover, the relatively low frequency of BRAF mutations brings into question if it actually plays a key role in melanoma pathogenesis.

BRAF Mutation Is Rare in Advanced-Stage Low-Grade Ovarian Serous Carcinomas

Low-grade ovarian serous carcinomas are believed to arise via an adenoma-serous borderline tumor-serous carcinoma sequence. In this study, we found that advanced-stage, low-grade ovarian serous carcinomas both with and without adjacent serous borderline tumor shared similar regions of loss of heterozygosity. We then analyzed 91 ovarian tumor samples for mutations in TP53, BRAF, and KRAS. TP53 mutations were not detected in any serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43) but were found in 73% of high-grade serous carcinomas (n = 18). BRAF (n = 9) or KRAS (n = 5) mutation was detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas (39 stage III, 2 stage II, and 2 stage I), only one (2%) had a BRAF mutation and eight (19%) had a KRAS mutation. The low frequency of BRAF mutations in advanced-stage, low-grade serous carcinomas, which contrasts with previous findings, suggests that aggressive, low-grade serous carcinomas are more likely derived from serous borderline tumors without BRAF mutation. In addition, advanced-stage, low-grade carcinoma patients with BRAF or KRAS mutation have a better apparent clinical outcome. However, further investigation is needed.

Abstract 2129A: Clinical implications of infrequent BRAF mutation in advanced stage low-grade ovarian serous carcinomas

Abstract Serous carcinoma is the most common histologic subtype of epithelial ovarian cancer. Recent evidence strongly suggests that a 2-tier system stratifying serous carcinoma into low-grade and high-grade categories is biologically and clinically relevant. Low-grade ovarian serous carcinomas are believed to arise via an adenoma-borderline-carcinoma sequence. We analyzed 91 ovarian tumor samples for mutations in BRAF, KRAS, and TP53. No TP53 mutations were detected in serous borderline tumors (n = 30) or low-grade serous carcinomas (n = 43), but 73% of high-grade serous carcinomas (n = 18) carried a TP53 mutation. BRAF and KRAS mutations together were detected in 47% of serous borderline tumors, but among the low-grade serous carcinomas, only 2% had a BRAF mutation and 19% had a KRAS mutation. The low frequency of BRAF mutations in advanced stage low-grade serous carcinomas suggests that low-grade serous carcinomas are likely derived from serous borderline tumors without BRAF mutations. This hypothesis is further supported by the fact that 2 of the patients with serous borderline tumors without BRAF or KRAS mutations developed recurrent low-grade serous carcinoma 17 and 60 months after the initial diagnosis of a serous borderline tumor. Moreover, it is interesting that 4 of the 8 patients with either BRAF or KRAS mutations have had no evidence of disease after optimal debulking surgery and standard platinum-taxane-based chemotherapy, while patients without mutations are either diseased or alive with recurrent disease. Thus, mutational analysis of BRAF may have prognostic utility in that a finding of a BRAF mutation may suggest a low risk of recurrent low-grade serous carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2129A.

Esophageal melanomas harbor frequent NRAS mutations unlike melanomas of other mucosal sites

Mucosal melanomas have genetic alterations distinct from those in cutaneous melanomas. For example, NRAS- and BRAF-activating mutations occur frequently in cutaneous melanomas, but not in mucosal melanomas. We examined 16 esophageal melanomas for genetic alterations in NRAS, BRAF, and KIT to determine whether they exhibit genetic features common to melanomas arising from other mucosal sites. A sequencing analysis identified NRAS mutations in six cases; notably, four of these mutations were located in exon 1, an uncommon mutation site in cutaneous and other mucosal melanomas. BRAF and KIT mutations were found in one case each. Immunohistochemistry showed KIT expression in four cases, including the tumor with a KIT mutation and two other intramucosal tumors. The low frequency of BRAF mutations and the presence of a KIT mutation-positive case are findings similar to those of mucosal melanomas of other sites, but the prevalence of NRAS mutations was even higher than that of cutaneous melanomas. The present study implies that esophageal melanomas have genetic alterations unique from those observed in other mucosal melanomas.

Low Frequency of BRAF Mutations in Endometrial and in Cervical Carcinomas

To the Editor:BRAF, which encodes a RAF family member that functions downstream of RAS, has been reported to be somatically mutated in a number of human cancers, most frequently at codon 599 (1). Activating mutations of BRAF have been frequently observed in colorectal carcinomas with microsatellite instability (MSI; ref. 2). In addition, mutations of BRAF and KRAS have been reported as being mutually exclusive in colorectal carcinomas (2). Mutations in BRAF have been studied in gynecological cancer. They are common in low-grade ovarian serous carcinoma, in which they provide an alternative route for activation of the RAS signaling pathway (3). In contrast, BRAF mutations have not been found in either other histological types of ovarian carcinomas or in cervical carcinomas (4).In the September 2005 issue of Clinical Cancer Research, Feng et al. reported a 21% incidence of BRAF mutations among 97 endometrial, 78 endometrioid (EEC), and 19 nonendometrioid carcinomas (5). In addition, one out of nine (11%) atypical endometrial hyperplasias also featured a BRAF mutation, most of which were located at previously unreported sites. In this series, there were no apparent differences in the prevalence of BRAF mutations among different stages, histological subtypes, and grades. The authors found 2 mutations in nonendometrioid carcinomas (11%) and 18 mutations in EECs (23%). Interestingly, BRAF mutations were more frequently found among tumors that negatively stained for hMLH1 (12 out of 32; 41%), suggesting an association between these BRAF mutations and MSI.These findings are in clear contradiction with those of three recent series exhibiting a low frequency of BRAF mutations in EEC. Thus, Mutch et al. (6) reported a single mutation among 146 EECs, which were also evaluated for KRAS mutations and MSI. This mutation occurred in 1 of the 81 MSI-positive cases. Salvesen et al. (7) studied BRAF mutations in 48 endometrial carcinomas and found one mutation in an MSI-negative EEC. In addition, Pappa et al. (4) found no mutations among the 67 endometrial carcinomas they analyzed.We have determined the incidence of BRAF mutations in exons 11 and 15 by PCR/single-strand conformational polymorphism and sequencing in a series of endometrial lesions previously characterized for KRAS, PTEN, and β-catenin mutations and MSI status (8). BRAF mutations were found in 1 of 19 atypical endometrial hyperplasias (5.6%) at codon 598 (T598I) as well as in 2 out of 94 EECs (2.1%) at codons 470 (S470F) and 614 (G614E), respectively. We also analyzed a series of 61 cervical carcinomas (19 squamous cell carcinomas and 42 adenocarcinomas) but did not find any BRAF mutations in the exons studied.With respect to cervical cancer, our results are in accordance with those reported by Pappa et al., who did not find any BRAF mutations among 47 cases, including squamous cell carcinomas and adenocarcinomas. Concerning endometrial carcinomas, our data are in close agreement with those of Pappa et al. (4), Mutch et al. (6) and Salvesen et al. (7), which indicate a low prevalence of BRAF mutation in these tumors. Differences between these series and that reported by Feng et al. (5) are difficult to explain because all of them featured an analysis of exons 11 and 15. One possible explanation may be the different ethnicity of the populations studied, whereby BRAF seems to have a more important role in Chinese patients. This is improbable, however, because the frequency of other molecular alterations, such as RAS and MSI, was very similar in all studies.In conclusion, most of the series analyzed thus far have shown a low prevalence of BRAF mutations in endometrial carcinomas, and an absence of association with other frequent molecular alterations, such as KRAS, PTEN, and MSI.In response: We thank Moreno-Bueno et al. for the letter in response to our recent article in Clinical Cancer Research (1). With regard to the differences in the incidence of BRAF mutations compared with other reports, we consider the following reasons:

Low Frequency of BRAF Mutations in Adult Patients with Papillary Thyroid Cancers Following Childhood Radiation Exposure

Radiation exposure at a young age is the only environmental factor known to cause thyroid cancer, predominantly of the papillary type. We have previously reported a high percentage (86.7%) of RET-positive papillary thyroid cancers in a cohort of individuals exposed to external radiation of the head and neck area before the age of 16. Recently, we and others have reported that point mutations of the BRAF gene occur with high frequency among sporadic adult papillary thyroid carcinomas, but occur at a much lower frequency in the population exposed after the Chernobyl accident. We here report that there is a similar low frequency of BRAF mutations among our cohort of those exposed to external beam radiation as children who later developed papillary thyroid cancer as adults. Samples were analyzed by mutation allele-specific amplification (MASA) for the most common T1799A mutation in exon 15 that converts amino acid 600 from valine to glutamate. In 23 cases, only 1 sample was positive. These results are further evidence that BRAF mutations, while common in sporadic adult papillary thyroid cancers, are rare events in cancers seen in subjects exposed to radiation as children.