Gene Summary

Gene:SNRPE; small nuclear ribonucleoprotein polypeptide E
Aliases: SME, Sm-E, B-raf, HYPT11
Databases:OMIM, HGNC, GeneCard, Gene
Protein:small nuclear ribonucleoprotein E
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Microsatellite Repeats
  • Recombinant Fusion Proteins
  • Transfection
  • Pedigree
  • Adolescents
  • Alleles
  • Sulfites
  • Molecular Sequence Data
  • DNA-Binding Proteins
  • Lung Cancer
  • Cell Cycle Proteins
  • Cancer Gene Expression Regulation
  • Chromosome 1
  • Genetic Predisposition
  • DNA Methylation
  • Autoantigens
  • Genomic Imprinting
  • Vincristine
  • Base Sequence
  • Childhood Cancer
  • Long Noncoding RNA
  • Proteins
  • Tumor Suppressor Proteins
  • Nuclear Proteins
  • Infant
  • snRNP Core Proteins
  • Transcription Factors
  • Gene Expression Profiling
  • Ovarian Cancer
  • Newborns
  • IGF2
  • Chromosome 11
  • Chromosome Aberrations
  • Ribonucleoproteins, Small Nuclear
  • Cancer DNA
  • Genome, Human
  • Gene Expression
  • Kruppel-Like Transcription Factors
  • Polymerase Chain Reaction
  • RNA, Untranslated
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SNRPE (cancer-related)

Asl JM, Almasi S, Tabatabaiefar MA
High frequency of BRAF proto-oncogene hot spot mutation V600E in cohort of colorectal cancer patients from Ahvaz City, southwest Iran.
Pak J Biol Sci. 2014; 17(4):565-9 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the most common forms of cancer around the world. Sporadic CRCs are caused by accumulation of mutations in essential genes regulating normal proliferation and differentiation of cells. The proto-oncogene BRAF encoded by the BRAF gene is involved in the RAS/RAF/MAPK pathway of signal transduction during cell growth. Acquired mutations in BRAF have been found at high frequencies in adult patients with papillary thyroid carcinoma and sporadic CRC. One of the predominant hot spot point mutations is T1799A (V600E) mutation among a cohort of CRC patients from Ahvaz city, southwest Iran. The aim of this study was to estimate the frequency of V600E mutation in CRC patients from Ahvaz city, southwest Iran. We analyzed exon 15 of the BRAF gene in isolated DNA from 80 Formalin Fixed Paraffin-embedded (FFPE) CRC tumor tissues using PCR-RFLP method. Data were analyzed using SPSS statistical program. According to our results 37 out of 80 cases (46.25%) were heterozygous for the mutation while the remaining 43 cases (53.75%) had normal homozygous genotype. No homozygous mutant genotype was found. Based on our findings, the frequency of V600E mutation appears to be significantly increased among CRC patients of the studied population but there was no significant relationship between genotypes and age and sex. In conclusion, these findings might prove the effect of V600E mutation on CRC pathogenesis. However, the exact effect of the mutation in CRC progression requires further work.

Bhatia P, Deniwar A, Friedlander P, et al.
Diagnostic potential of ancillary molecular testing in differentiation of benign and malignant thyroid nodules.
Anticancer Res. 2015; 35(3):1237-41 [PubMed] Related Publications
Fine needle aspiration (FNA) cytology, being the mainstay to diagnose thyroid nodules, does not provide definitive results in a subset of patients. The use of molecular markers testing has been described as a useful aid in differentiation of thyroid nodules that present with an indeterminate cytodiagnosis. Molecular tests, such as the Afirma gene classifier, mutational assay and immunohistochemical markers have been increasingly used to further increase the accuracy and defer unnecessary surgeries for benign thyroid nodules. However, in light of the current literature, their emerging roles in clinical practice are limited due to financial and technical limitations. Nevertheless, their synergistic implementation can predict the risk of malignancy and yield an accurate diagnosis. This review discusses the clinical utility of various molecular tests done on FNA indeterminate nodules to avoid diagnostic thyroidectomies and warrant the need of future multi-Institutional studies.

Pilozzi E, Maresca C, Duranti E, et al.
Left-sided early-onset vs late-onset colorectal carcinoma: histologic, clinical, and molecular differences.
Am J Clin Pathol. 2015; 143(3):374-84 [PubMed] Related Publications
OBJECTIVES: Carcinomas of the left colon represent a neoplasm of older patients (late onset), but epidemiologic evidence has been showing an increasing incidence in patients 50 years or younger (early onset). In this study, we investigate pathologic and molecular features of early- and late-onset carcinoma of the left colon.
METHODS: We selected 22 patients 50 years or younger and 21 patients 70 years or older with left-sided colorectal carcinoma (CRC). All samples were evaluated for pathologic features, microsatellite instability, and KRAS and BRAF mutations. Moreover, both groups were analyzed to identify CpG island methylator phenotype features and assessed with restriction landmark genome scanning (RLGS) to unveil differential DNA methylation patterns.
RESULTS: Early-onset patients had advanced pathologic stages compared with late-onset patients (P = .0482). All cases showed a microsatellite stable profile and BRAF wild-type sequence. Early-onset patients (43%) more frequently had mutations at KRAS codon 12 compared with late-onset patients (14%) (P =.0413). RLGS showed that patients younger than 50 years who had CRC had a significantly lower percentage of methylated loci than did patients 70 years or older (P = .04124), and differential methylation of several genomic loci was observed in the two groups.
CONCLUSIONS: Our results suggest that left-sided CRCs may present differential patterns of aberrant DNA methylation when they are separated by age.

Lee J, Jeong S, Park JH, et al.
Aberrant expression of COT is related to recurrence of papillary thyroid cancer.
Medicine (Baltimore). 2015; 94(6):e548 [PubMed] Related Publications
Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n = 167) and analyze the clinical implications of aberrant expression of these genes.Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).qPCR data showed that the relative mRNA expression of A-, B-, C-RAF and COT of PTC were higher than normal tissues (all P < 0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (r = 0.4083, P < 0.001), B- (r = 0.2773, P = 0.0003), and C-RAF (r = 0.5954, P < 0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all P < 0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (P < 0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF-positive PTC (P < 0.001, P = 0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (P = 0.045) and higher recurrence rate (P = 0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF mutation (odds ratio, 4.662; 95% confidence interval 1.066 - 21.609; P = 0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2 ± 4.1 years; P = 0.0403). GSEA indicated that gene sets related to B-RAF-RAS (P < 0.0001, false discovery rate [FDR] q-value = 0.000) and thyroid differentiation (P = 0.048, FDR q-value = 0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, P < 0.0001, FDR q-value = 0.000).Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.

Mistry M, Zhukova N, Merico D, et al.
BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma.
J Clin Oncol. 2015; 33(9):1015-22 [PubMed] Article available free on PMC after 20/03/2016 Related Publications
PURPOSE: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG).
PATIENTS AND METHODS: We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained.
RESULTS: sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024).
CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.

Lopez-Chavez A, Thomas A, Rajan A, et al.
Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial.
J Clin Oncol. 2015; 33(9):1000-7 [PubMed] Article available free on PMC after 20/03/2016 Related Publications
PURPOSE: We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently.
PATIENTS AND METHODS: We enrolled patients with advanced non-small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification.
RESULTS: Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years).
CONCLUSION: This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

Perna D, Karreth FA, Rust AG, et al.
BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model.
Proc Natl Acad Sci U S A. 2015; 112(6):E536-45 [PubMed] Article available free on PMC after 20/03/2016 Related Publications
BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors elicit a transient anti-tumor response in ∼ 80% of BRAF(V600)-mutant melanoma patients that almost uniformly precedes the emergence of resistance. Here we used a mouse model of melanoma in which melanocyte-specific expression of Braf(V618E) (analogous to the human BRAF(V600E) mutation) led to the development of skin hyperpigmentation and nevi, as well as melanoma formation with incomplete penetrance. Sleeping Beauty insertional mutagenesis in this model led to accelerated and fully penetrant melanomagenesis and synchronous tumor formation. Treatment of Braf(V618E) transposon mice with the BRAF inhibitor PLX4720 resulted in tumor regression followed by relapse. Analysis of transposon insertions identified eight genes including Braf, Mitf, and ERas (ES-cell expressed Ras) as candidate resistance genes. Expression of ERAS in human melanoma cell lines conferred resistance to PLX4720 and induced hyperphosphorylation of AKT (v-akt murine thymoma viral oncogene homolog 1), a phenotype reverted by combinatorial treatment with PLX4720 and the AKT inhibitor MK2206. We show that ERAS expression elicits a prosurvival signal associated with phosphorylation/inactivation of BAD, and that the resistance of hepatocyte growth factor-treated human melanoma cells to PLX4720 can be reverted by treatment with the BAD-like BH3 mimetic ABT-737. Thus, we define a role for the AKT/BAD pathway in resistance to BRAF inhibition and illustrate an in vivo approach for finding drug resistance genes.

Netter J, Lehmann-Che J, Lambert J, et al.
Functional TP53 mutations have no impact on response to cytotoxic agents in metastatic colon cancer.
Bull Cancer. 2015; 102(2):117-25 [PubMed] Related Publications
BACKGROUND: Survival of metastatic colon cancer (mCC) patients has considerably improved with optimization of new drugs regimen. Inactivation of TP53 pathway by TP53 mutations is observed in nearly half of colorectal tumors. The impact of such mutations has been poorly studied in the metastatic setting.
METHODS: The files of 254 mCC treated in a single institution at Saint-Louis hospital between January 1999 and April 2011 were retrospectively reviewed. Tissue samples for analysis of TP53 mutations were available for 68 patients, performed using FASAY. The prognostic value of TP53 status was evaluated by comparing progression free survival (PFS) and overall survival (OS) in the group of TP53-mutated and wild type patients.
RESULTS: PFS was 6.9 months and OS 21.7 months in the whole population. There was no statistical difference in TP53-mutated and wild type groups in term of PFS (HR=1.04; IC 95%=0.6-1.79) and OS (HR=0.99; IC 95%=0.53-1.55) whatever the chemotherapy regimen (oxaliplatin- or irinotecan-based). Only BRAF V600 mutation was demonstrated to be a poor prognostic factor for PFS and OS, and CEA level for OS.
CONCLUSIONS: Routine determination of TP53 mutations, even with a highly sensitive method, cannot be recommended to predict chemotherapy response in mCC.

Tan JM, Lin LL, Lambie D, et al.
BRAF wild-type melanoma in situ arising in a BRAF V600E mutant dysplastic nevus.
JAMA Dermatol. 2015; 151(4):417-21 [PubMed] Related Publications
IMPORTANCE: The BRAF V600E mutation accounts for the majority of BRAF mutations found in cutaneous melanoma and is also commonly found in nevi. We used dermoscopy-targeted sampling and a microbiopsy device coupled with DNA sequence analysis to highlight BRAF V600E heterogeneity within a multicomponent melanocytic proliferation. This sampling technique demonstrates the prospect of in vivo application in a clinical setting.
OBSERVATIONS: A man in his 50s with Fitzpatrick skin type II presented with an irregularly pigmented melanocytic lesion on his back that met melanoma-specific dermoscopic criteria, and diagnostic shave excision of the lesion was performed. Histopathologic analysis revealed a melanoma in situ arising in a dysplastic nevus. Dermoscopy-targeted microbiopsy specimens were taken across the lesion, and genotyping was carried out on extracted DNA samples for BRAF and NRAS mutations. The melanoma in situ showed only BRAF wild-type results, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype.
CONCLUSIONS AND RELEVANCE: Dermoscopy-targeted sampling and genotyping of a melanoma in situ arising in a dysplastic nevus revealed a phenotype-genotype paradox that confounds the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis. Further studies are required to investigate the importance of other candidate genes linked to melanomagenesis.

Eriksson H, Zebary A, Vassilaki I, et al.
BRAFV600E protein expression in primary cutaneous malignant melanomas and paired metastases.
JAMA Dermatol. 2015; 151(4):410-6 [PubMed] Related Publications
IMPORTANCE: BRAFV600E mutations are present in approximately 50% of cutaneous malignant melanomas (CMMs). The use of BRAFV600E mutation-specific monoclonal antibody VE1 immunohistochemical analysis may facilitate rapid detection of BRAFV600E mutations in CMMs and demonstrate heterogeneity among tumors.
OBJECTIVES: To characterize the pattern of BRAFV600E protein expression in primary CMMs with matched metastases and to analyze the use of VE1 immunohistochemical analysis in clinical practice using formalin-fixed, paraffin-embedded tumor tissue.
DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study performed at Karolinska University Hospital from September 2012 to September 2013, we examined CMMs (124 primary tumors and 76 metastases) with VE1 immunohistochemical analysis, and results were compared with DNA mutation analyses.
MAIN OUTCOMES AND MEASURES: Determination of intratumoral and intertumoral heterogeneity as well as the sensitivity and specificity of VE1 immunohistochemical analysis.
RESULTS: Positive staining results with the VE1 antibody were detected in 94 of 200 tumors (47.0%). In general, VE1 staining was homogeneous. However, VE1 staining intensity varied among the primary tumors and corresponding metastases in 63 of 135 tumors (46.7%), but a change of mutational status based on DNA analysis was found in only 4 matched tumors (3.0%). Discordant findings between DNA mutation analysis and immunohistochemical analysis were observed in 12 tumors. The overall sensitivity and specificity of VE1 immunohistochemical analysis were 96.7% and 94.5%, respectively. A comparable sensitivity was obtained for primary and metastatic CMMs. The specificity was lower among primary CMMs (92.4%) compared with metastases (98.0%).
CONCLUSIONS AND RELEVANCE: We found VE1 immunohistochemical analysis to be a useful and rapid assay for BRAFV600E mutations that may contribute to the detection of intratumoral and intertumoral heterogenetic subclones. Tumors with positive results, including strong staining, should be expedited for confirmatory BRAF mutation testing. If this test result is negative, a false-negative result of the mutation analysis should be considered. Validation of VE1 immunohistochemical analysis in clinical practice is needed.

Della Pepa C, Tonini G, Santini D, et al.
Low Grade Serous Ovarian Carcinoma: from the molecular characterization to the best therapeutic strategy.
Cancer Treat Rev. 2015; 41(2):136-43 [PubMed] Related Publications
Low Grade Serous Ovarian Carcinoma, LGSOC, is certainly a rare disease, accounting for only a small proportion of all ovarian carcinomas, nevertheless in the last decade we have acquired many data about its molecular and clinical features and it has been largely accepted that it has distinct pathogenesis, genetic aberrations and clinical behavior compared to High Grade Serous Ovarian Carcinoma, HGSOC, which is the most common ovarian cancer histotype. A large number of series pointed out the high rate of KRAS and BRAF mutations in LGSOCs and Serous Borderline Tumors, SBLTs, in contrast with their rarity in HGSOC. Such finding, together with the recurrent observation of focus of LGSOC associated with areas of SBLT in the same lesion, led to abandon the traditional histology classification, defining three types of serous carcinomas, in favor of a new dualistic grading system which recognizes only LG and HG carcinomas corresponding to distinct tumorigenesis pathways, the former based on KRAS/BRAF mutations and alteration of the MAP/ERK signaling, the latter characterized by early genetic instability and wild type status of KRAS and BRAF. LGSOC shows favorable overall survival, compared to general ovarian cancer population, but worrying resistance to conventional treatments. MEK inhibitors are emerging as active agents and may well represent an effective therapeutic strategy in the near future.

Griewank KG, Schadendorf D
Panel sequencing melanomas.
J Invest Dermatol. 2015; 135(2):335-6 [PubMed] Related Publications
Sequencing samples of melanoma for targetable mutations has become a standard of care for metastatic disease. In this issue, Siroy et al. demonstrate how clinical genetic analysis is moving from a single-gene Sanger-sequencing approach to targeted next-generation sequencing. They present data on a large cohort of patients with advanced melanoma, and their data support previous findings and also present novel aspects of melanoma genetics.

Iacovelli S, Hug E, Bennardo S, et al.
Two types of BCR interactions are positively selected during leukemia development in the Eμ-TCL1 transgenic mouse model of CLL.
Blood. 2015; 125(10):1578-88 [PubMed] Article available free on PMC after 05/03/2016 Related Publications
Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable course and outcome. The disease is believed to be driven by B-cell receptor (BCR) signals generated by external antigens and/or cell-autonomous BCR interactions, but direct in vivo evidence for this is still lacking. To further define the role of the BCR pathway in the development and progression of CLL, we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in the Eμ-TCL1 transgenic mouse model. We show that cell autonomous signaling capacity is a uniform characteristic of the leukemia-derived BCRs and represents a prerequisite for CLL development. Low-affinity BCR interactions with autoantigens generated during apoptosis are also positively selected, suggesting that they contribute to the pathogenesis of the disease. In contrast, high-affinity BCR interactions are not selected, regardless of antigen form or presentation. We also show that the capacity of the leukemic cells to respond to cognate antigen correlates inversely with time to leukemia development, suggesting that signals induced by external antigen increase the aggressiveness of the disease. Collectively, these findings provide in vivo evidence that the BCR pathway drives the development and can influence the clinical course of CLL.

Shen AS, Peterhof E, Kind P, et al.
Activating mutations in the RAS/mitogen-activated protein kinase signaling pathway in sporadic trichoblastoma and syringocystadenoma papilliferum.
Hum Pathol. 2015; 46(2):272-6 [PubMed] Related Publications
Trichoblastoma (TB) and syringocystadenoma papilliferum (SCAP) are both rare adnexal skin lesions occurring either sporadically or as secondary neoplasms in sebaceous nevi. TB and SCAP associated with sebaceous nevi have been shown to carry the same HRAS mutation as the underlying nevus. However, the genetic background of sporadic TB and SCAP has remained unknown. Therefore, we screened 18 sporadic TBs and 23 sporadic syringocystadenoma papillifera from 41 patients for the presence of activating mutations in RAS genes and other oncogenes. Using a RAS SNaPshot assay, HRAS mutations were detected in 2 (11%) of 18 sporadic TB and 6 (26%) of 23 sporadic syringocystadenoma papillifera. A KRAS mutation was identified in 1 sporadic SCAP. High-throughput oncogene mutation profiling furthermore identified BRAF V600E mutations in sporadic syringocystadenoma papillifera, which could be validated in 12 (52%) of 23 lesions using a BRAF SNaPshot assay. BRAF and RAS mutations were mutually exclusive in sporadic syringocystadenoma papillifera. No BRAF mutation could be detected in 3 syringocystadenoma papillifera secondarily arisen from a sebaceous nevus as well as in sporadic TB. In 14 lesions carrying an oncogenic mutation, nonlesional control tissue from the epidermal margin revealed a wild-type sequence, thus proving the somatic character of the mutation. Our results indicate that activation of the RAS-mitogen-activated protein kinase pathway by BRAF and RAS mutations contributes significantly to the tumorigenesis of sporadic SCAP and, less frequently, of sporadic TB.

Brown NA, Betz BL, Weigelin HC, et al.
Evaluation of allele-specific PCR and immunohistochemistry for the detection of BRAF V600E mutations in hairy cell leukemia.
Am J Clin Pathol. 2015; 143(1):89-99 [PubMed] Related Publications
OBJECTIVES: Detection of BRAF V600E mutations in hairy cell leukemia (HCL) has important diagnostic utility. In this study, we sought to compare immunohistochemistry with an antibody specific for this mutation to a sensitive molecular assay.
METHODS: The performance of the BRAF V600E-specific VE1 antibody was compared with that of allele-specific polymerase chain reaction (PCR) in 22 formalin-fixed, paraffin-embedded (FFPE) specimens with HCL involvement, along with nine splenic marginal zone lymphomas (SMZLs), 10 follicular lymphomas (FLs), 10 mantle cell lymphomas (MCLs), and 10 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLLs). An additional 11 SMZLs, 100 FLs, 20 MCLs, 83 CLL/SLL specimens, and 49 reactive tonsils within tissue microarrays were stained with VE1.
RESULTS: A BRAF V600E mutation was detected in 17 (77.3%) of 22 HCL cases by PCR. Immunohistochemistry demonstrated VE1 staining in 20 (90.9%) cases, identifying low-level (~1%) involvement in three HCL cases that were mutation negative by PCR. Evaluation of additional material from these patients confirmed the presence of BRAF V600E. Thirty-nine non-HCL cases were negative by both methods. Within tissue microarrays, weak false-positive staining was observed in two (0.8%) of 263 non-HCL cases.
CONCLUSIONS: VE1 immunohistochemistry is more sensitive than allele-specific PCR in FFPE bone marrow specimens and can be applied to decalcified core biopsy specimens that are not appropriate for molecular techniques.

Girotti MR, Lopes F, Preece N, et al.
Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.
Cancer Cell. 2015; 27(1):85-96 [PubMed] Article available free on PMC after 05/03/2016 Related Publications
BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.

Konermann S, Brigham MD, Trevino AE, et al.
Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex.
Nature. 2015; 517(7536):583-8 [PubMed] Article available free on PMC after 05/03/2016 Related Publications
Systematic interrogation of gene function requires the ability to perturb gene expression in a robust and generalizable manner. Here we describe structure-guided engineering of a CRISPR-Cas9 complex to mediate efficient transcriptional activation at endogenous genomic loci. We used these engineered Cas9 activation complexes to investigate single-guide RNA (sgRNA) targeting rules for effective transcriptional activation, to demonstrate multiplexed activation of ten genes simultaneously, and to upregulate long intergenic non-coding RNA (lincRNA) transcripts. We also synthesized a library consisting of 70,290 guides targeting all human RefSeq coding isoforms to screen for genes that, upon activation, confer resistance to a BRAF inhibitor. The top hits included genes previously shown to be able to confer resistance, and novel candidates were validated using individual sgRNA and complementary DNA overexpression. A gene expression signature based on the top screening hits correlated with markers of BRAF inhibitor resistance in cell lines and patient-derived samples. These results collectively demonstrate the potential of Cas9-based activators as a powerful genetic perturbation technology.

Pettirossi V, Santi A, Imperi E, et al.
BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity.
Blood. 2015; 125(8):1207-16 [PubMed] Article available free on PMC after 05/03/2016 Related Publications
Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL.

Piris A, Mihm MC, Hoang MP
BAP1 and BRAFV600E expression in benign and malignant melanocytic proliferations.
Hum Pathol. 2015; 46(2):239-45 [PubMed] Related Publications
BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene whose mutations have recently been reported to increase susceptibility for the development of uveal melanoma, cutaneous atypical and epithelioid melanocytic lesions, clear cell renal cell carcinoma, and other tumors. Screening for BAP1 mutation/loss/inactivation and BRAFV600E mutation can be done by immunohistochemistry. We investigated BAP1 and BRAFV600E expression in 193 sporadic melanocytic lesions (11 dermal nevi, 20 congenital nevi, 40 primary and nondesmoplastic melanomas, 40 desmoplastic melanomas, 23 metastatic melanomas, 17 Spitz nevi, 19 atypical Spitz nevi, 8 atypical Spitz tumors, 14 proliferative nodules arising in congenital nevi, 1 nevus during pregnancy) and 30 melanocytic lesions from 3 patients with family history of uveal melanoma and BAP1 germline mutation. Most sporadic melanocytic lesions exhibited positive BAP1 nuclear staining, except for 1 proliferative nodule arising in congenital nevus, 1 desmoplastic, 1 nevoid, and 2 metastatic melanomas. BRAFV600E positivity was demonstrated in 80% of dermal, 5% of congenital, 6% of Spitz, and 5.5% of atypical Spitz nevi; 29% of proliferative nodules arising in congenital nevi; and 24% of primary and nondesmoplastic and 35% of metastatic melanomas. Combined BAP1 loss and BRAFV600E staining was seen in 67% of BAP1 tumor syndrome-associated lesions and in none of the sporadic melanocytic proliferations including Spitz and atypical Spitz nevi and atypical Spitz tumors, with the exception of 1 primary melanoma. The combined BAP1-BRAFV600E+ immunoprofile appears to be a constant feature of BAP1 tumor syndrome-associated melanocytic lesions, and the designation of Spitz nevi or variants thereof appears to be inaccurate for this group of lesions.

Kalia M
Biomarkers for personalized oncology: recent advances and future challenges.
Metabolism. 2015; 64(3 Suppl 1):S16-21 [PubMed] Related Publications
Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells and oncology is a branch of medicine that deals with tumors. The last decade has seen significant advances in the development of biomarkers in oncology that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression. Clinical molecular diagnostics and biomarker discoveries in oncology are advancing rapidly as we begin to understand the complex mechanisms that transform a normal cell into an abnormal one. These discoveries have fueled the development of novel drug targets and new treatment strategies. The standard of care for patients with advanced-stage cancers has shifted away from an empirical treatment strategy based on the clinical-pathological profile to one where a biomarker driven treatment algorithm based on the molecular profile of the tumor is used. Recent advances in multiplex genotyping technologies and high-throughput genomic profiling by next-generation sequencing make possible the rapid and comprehensive analysis of the cancer genome of individual patients even from very little tumor biopsy material. Predictive (diagnostic) biomarkers are helpful in matching targeted therapies with patients and in preventing toxicity of standard (systemic) therapies. Prognostic biomarkers identify somatic germ line mutations, changes in DNA methylation, elevated levels of microRNA (miRNA) and circulating tumor cells (CTC) in blood. Predictive biomarkers using molecular diagnostics are currently in use in clinical practice of personalized oncotherapy for the treatment of five diseases: chronic myeloid leukemia, colon, breast, lung cancer and melanoma and these biomarkers are being used successfully to evaluate benefits that can be achieved through targeted therapy. Examples of these molecularly targeted biomarker therapies are: tyrosine kinase inhibitors in chronic myeloid leukemia and gastrointestinal tumors; anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALk fusion; HER2/neu blockage in HER2/neu-positive breast cancer; and epidermal growth factor receptors (EGFR) inhibition in EGFR-mutated lung cancer. This review presents the current state of our knowledge of biomarkers in five selected cancers: chronic myeloid leukemia, colorectal cancer, breast cancer, non-small cell lung cancer and melanoma.

Chai YJ, Kim YA, Jee HG, et al.
Expression of the embryonic morphogen Nodal in differentiated thyroid carcinomas: Immunohistochemistry assay in tissue microarray and The Cancer Genome Atlas data analysis.
Surgery. 2014; 156(6):1559-67; discussion 1567-8 [PubMed] Related Publications
BACKGROUND: Nodal, an embryonic morphogen, plays a role in tumorigenesis of melanoma, breast, and prostate cancer; however, its role in thyroid carcinoma is unknown. We examined Nodal expression in thyroid tumors by immunohistochemistry assay and The Cancer Genome Atlas (TCGA) analysis.
METHODS: An immunohistochemistry assay was performed in a tissue microarray comprising 128 classic papillary thyroid carcinomas (PTC), 58 follicular thyroid carcinomas (FTC), 19 follicular variants of PTC (FVPTC), 57 follicular adenomas (FA), 54 adenomatous goiters (AG), and 5 normal thyroid tissues. The TCGA database was examined to evaluate the expression of Nodal mRNA in normal thyroid and PTC.
RESULTS: The proportion of tumors showing negative Nodal expression in PTC, FTC, FVPTC, FA, and AG was 0%, 1.7%, 0%, 14%, and 41%, respectively. For the diagnosis of malignant tumors, the sensitivity, specificity, positive predictive value, and negative predictive value of positive Nodal staining was 99%, 27%, 72%, and 97%, respectively. High Nodal expression was associated with older age and BRAF mutation in PTC. TCGA analysis revealed PTC had greater Nodal mRNA expression than normal thyroid (P = .012).
CONCLUSION: Nodal staining might be useful "rule-out test" for the diagnosis of malignant thyroid tumor. Nodal may be associated with the tumorigenesis of thyroid malignancy.

Miccoli P, Torregrossa L, Borrelli N, et al.
E-selectin expression and BRAF status in papillary thyroid carcinomas: Correlation with clinicopathologic features.
Surgery. 2014; 156(6):1550-7; discussion 1557-8 [PubMed] Related Publications
BACKGROUND: Cell adhesion molecules, represented by the immunoglobulin family and selectins, play an important role in the progression of cancer. A correlation between selectins and tumor aggressiveness has been demonstrated in several reports.
METHODS: Eighty-eight patients (mean age, 41.0 ± 14 years) with papillary thyroid carcinoma (conventional variant and sized approximately 20 mm) were divided in 2 groups: 41 with encapsulated tumors and 47 with tumors with extrathyroidal extension. E-selectin expression was evaluated by immunohistochemical staining and semiquantitative real-time reverse-transcription polymerase chain reaction and normalized by calculating the z-score (positive: value above the population mean; negative: below the mean).
RESULTS: Lymph node metastasis (LNM) was found in 2 of 41 encapsulated tumors (4.8%) and in 19 of 47 tumors (40.4%) with extrathyroidal extension. BRAF mutation was present in 21 encapsulated tumors (51.2%) and in 31 tumors with extrathyroidal extension (65.9%). The mean E-selectin z-score was -0.32 for encapsulated tumors and 0.28 for tumors with extrathyroidal extension. E-selectin expression correlates with neoplastic infiltration (P = .04), the American Joint Commission on Cancer stage (P = .02), and BRAF mutation (P = .03).
CONCLUSION: E-selectin overexpression in association with BRAF mutation status could promote a more aggressive phenotype in papillary thyroid carcinoma.

Caputo E, Wang E, Valentino A, et al.
Ran signaling in melanoma: implications for the development of alternative therapeutic strategies.
Cancer Lett. 2015; 357(1):286-96 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p ≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.

Arnedos M, Soria JC, Andre F, Tursz T
Personalized treatments of cancer patients: a reality in daily practice, a costly dream or a shared vision of the future from the oncology community?
Cancer Treat Rev. 2014; 40(10):1192-8 [PubMed] Related Publications
Therapies targeting activated oncogenes have been associated with several successes in the last decades that are described in this review, together with their limits and related unsolved questions. Most of the tumours will eventually develop drug resistance potentially due to intratumor heterogeneity and selection of additional molecular events. Moreover, studies in the field of molecular characterisation of cancers have shown that most tumors include large number of rare genomic events. Developing new drugs requires the use of large-scale molecular screening programs to enrich phase I/II trials with patients presenting the genetic alterations to treat them with the appropriate drug(s). Administering one single drug will incur in non-durable results, so the future is to cleverly combine drugs. Development of personalized immunotherapeutics and/or anti-angiogenic agents could change the natural history of several cancers. Finally, other systems including DNA repair and metabolism have become targetable. These considerations justify the development of molecular medicine with the characterisation of each tumour to assess defects in all the systems previously mentioned to propose a unique combination of therapies to each patient. Current drug development is clearly not appropriate, and studies with drugs given in relevant combinations should be favoured by new relationships between academia and industry. New organisational and medico-economics approaches are required to minimize the financial burden of personalized medicine by considering the foreseen decrease of the costs of new technologies, and the money saved by avoiding the use of many costly, useless but nonetheless toxic treatments given after failure of standard therapy.

Knief J, Gebauer N, Bernard V, et al.
Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B-cell lymphomas of the thyroid--a study of 21 cases.
J Clin Endocrinol Metab. 2015; 100(2):754-62 [PubMed] Related Publications
CONTEXT: Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored.
OBJECTIVE: Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations.
DESIGN: A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data.
RESULTS: Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups. Statistically significant deviations were detected at 20q13.33 and 21q11.2. These specific alterations do not seem to occur in thyroid carcinomas or other DLBCL, according to previously published literature. Analysis of BRAF and NRAS showed mutation frequencies of 4.8 and 9.5%, respectively. No MYD88 mutations could be detected in any of the analyzed cases. Fluorescence in situ hybridization demonstrated breakage events involving the BCL2, BCL6, and cMYC locus in 14.3, 9.5, and 9.5%, respectively.
CONCLUSIONS: Our study revealed ptDLBCL to be predominantly composed of the GCB type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. Additionally, array comparative genomic hybridization showed no overlapping alterations between ptDLBCL and thyroid carcinomas or other nodal or extranodal DLBCL.

Lv ZC, Ning JY, Chen HB
Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials.
Tumour Biol. 2014; 35(12):11741-50 [PubMed] Related Publications
Cetuxiamb, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the efficacy of combined therapies of cetuximab and different chemotherapy regimens remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and toxicity of adding cetuximab to oxaliplatin-based or irinotecan-based chemotherapeutic regimens for the treatment of patients with mCRC with wild-type/mutated KRAS tumors. Randomized controlled trials (RCTs), published in Pubmed and Embase were systematically reviewed to assess the survival benefits and toxicity profile mCRC patients treated with cetuximab plus chemotherapy. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95 % confidence intervals (CI). Pooled estimates were generated by using a fixed-effects model or a randomized-effects model, depending on the heterogeneity among studies. A total of 12 trials involving 6,297 patients met the inclusion criteria and were included in this meta-analysis. All patients were administered oxaliplatin-based or irinotecan-based chemotherapy with or without cetuximab. Pooled results showed that the addition of cetuximab did not significantly improve the OS (HR = 0.99, 95 % CI = 0.89-1.09; Z = 0.28, P = 0.78) or PFS (HR = 0.94, 95 % CI = 0.81-1.10; Z = 0.76, P = 0.49), but did improve ORR (RR = 1.34, 95 % CI = 1.08-1.65; Z = 2.72, P = 0.00), when compared with chemotherapy alone. Subgroup analysis showed the highest PFS benefit in patients with wild-type KRAS tumors (HR = 0.80, 95 % CI = 0.65-0.99; Z = 2.1, P = 0.04) or wild-type KRAS/BRAF tumors (HR = 0.64, 95 % CI = 0.52-0.79; Z = 4.15, P = 0.00). When combined with cetuximab, irinotecan-based chemotherapy was significantly associated with prolonged PFS (HR = 0.79, 95 % CI = 0.66-0.96; Z = 2.36, P = 0.02) for all patients with differing gene-status. The incidence of grade 3/4 adverse events, including skin toxicity, diarrhea, hypertension, anorexia, and mucositis/stomatitis, was slightly higher in the combined therapy group than in the chemotherapy-only group. Based on the current evidence, the addition of cetuximab to chemotherapy significantly improves the PFS in patients with wild-type KRAS or wild-type KRAS/BRAF tumors as well as the ORR in all patients. In addition, irinotecan-based combination therapy showed a beneficial effect on the PFS in all patients. These findings confirm the use of cetuximab in combination with chemotherapy for the treatment of patients with mCRC with wild-type KRAS tumors. Further multi-center RCTs are needed to indentify these findings.

Sanmamed MF, Fernández-Landázuri S, Rodríguez C, et al.
Quantitative cell-free circulating BRAFV600E mutation analysis by use of droplet digital PCR in the follow-up of patients with melanoma being treated with BRAF inhibitors.
Clin Chem. 2015; 61(1):297-304 [PubMed] Related Publications
BACKGROUND: Around 50% of cutaneous melanomas harbor the BRAF(V600E) mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as cell-free BRAF(V600E) (cfBRAF(V600E)). Droplet digital PCR (ddPCR) is an analytically sensitive technique for quantifying small concentrations of DNA. We studied the plasma concentrations of cfBRAF(V600E) by ddPCR in patients with melanoma during therapy with BRAF inhibitors.
METHODS: Plasma concentrations of cfBRAF(V600E) were measured in 8 controls and 20 patients with advanced melanoma having the BRAF(V600E) mutation during treatment with BRAF inhibitors at baseline, first month, best response, and progression.
RESULTS: The BRAF(V600E) mutation was detected by ddPCR even at a fractional abundance of 0.005% in the wild-type gene. Agreement between tumor tissue BRAF(V600E) and plasma cfBRAF(V600E) was 84.3%. Baseline cfBRAF(V600E) correlated with tumor burden (r = 0.742, P < 0.001). cfBRAF(V600E) concentrations decreased significantly at the first month of therapy (basal median, 216 copies/mL; Q1-Q3, 27-647 copies/mL; first response median, 0 copies/mL; Q1-Q3, 0-49 copies/mL; P < 0.01) and at the moment of best response (median, 0 copies/mL; Q1-Q3, 0-33 copies/mL; P < 0.01). At progression, there was a significant increase in the concentration of cfBRAF(V600E) compared with best response (median, 115 copies/mL; Q1-Q3, 3-707 copies/mL; P = 0.013). Lower concentrations of basal cfBRAF(V600E) were significantly associated with longer overall survival and progression-free survival (27.7 months and 9 months, respectively) than higher basal concentrations (8.6 months and 3 months, P < 0.001 and P = 0.024, respectively).
CONCLUSIONS: cfBRAF(V600E) quantification in plasma by ddPCR is useful as a follow-up to treatment response in patients with advanced melanoma.

Renaud F, Vincent A, Mariette C, et al.
MUC5AC hypomethylation is a predictor of microsatellite instability independently of clinical factors associated with colorectal cancer.
Int J Cancer. 2015; 136(12):2811-21 [PubMed] Related Publications
Colorectal cancers (CRC) with microsatellite instability (MSI) display unique clinicopathologic features including a mucinous pattern with frequent expression of the secreted mucins MUC2 and MUC5AC. The mechanisms responsible for this altered pattern of expression remain largely unknown. We quantified DNA methylation of mucin genes (MUC2, MUC5AC, MUC4) in colonic cancers and examined the association with clinicopathological characteristics and molecular (MSI, KRAS, BRAF, and TP53 mutations) features. A control cohort was used for validation. We detected frequent hypomethylation of MUC2 and MUC5AC in CRC. MUC2 and MUC5AC hypomethylation was associated with MUC2 and MUC5AC protein expression (p = 0.004 and p < 0.001, respectively), poor differentiation (p = 0.001 and p = 0.007, respectively) and MSI status (p < 0.01 and p < 0.001, respectively). Interestingly, MUC5AC hypomethylation was specific to MSI cancers. Moreover, it was significantly associated with BRAF mutation and CpG island methylator phenotype (p < 0.001 and p < 0.001, respectively). All these results were confirmed in the control cohort. In the multivariate analysis, MUC5AC hypomethylation was a highly predictive biomarker for MSI cancers. MUC5AC demethylation appears to be a hallmark of MSI in CRC. Determination of MUC5AC methylation status may be useful for understanding and predicting the natural history of CRC.

Carter CA, Nations JA, Lazarus A
Molecular targets in the treatment of non-small-cell lung cancer: is there hope on the horizon?
Postgrad Med. 2014; 126(7):139-48 [PubMed] Related Publications
Non-small-cell lung cancer (NSCLC) is a growing concern worldwide, and its incidence continues to increase in developing countries. It has a strong association with smoking. Lung cancer remains the leading cause of cancer-related deaths in most industrialized countries and in the United States. In the last 10 years, there have been significant advancements in the understanding of molecular oncogenes and how they play a role in driving lung cancer to both grow and metastasize. Understanding this rapidly expanding field has the potential to extend life, and it is an important field for all providers to conceptualize if they are treating patients with lung cancer. Currently, > 50% of all NSCLC is linked to 1 of several known genetic driver mutations. Using online databases, expert opinion, and practice-changing trials, we review the current standards of molecular testing of NSCLC and the expanding evidence of oncogenic drivers in nonsquamous NSCLC.

Antonelli M, Badiali M, Moi L, et al.
KIAA1549:BRAF fusion gene in pediatric brain tumors of various histogenesis.
Pediatr Blood Cancer. 2015; 62(4):724-7 [PubMed] Related Publications
The KIAA1549:BRAF fusion gene is considered a driver genetic event in pilocytic astrocytoma. We investigated a series of 69 pediatric brain neoplasms of diverse histogenesis and grade using the RT-PCR and sequencing. We detected the KIAA1549:BRAF fusion gene in five of 34 non-PA tumors (14.7%), that is, one glioblastoma, one anaplastic astrocytoma, one anaplastic pleomorphic xanthoastrocytoma, 1 ependymoma, and 1 Atypical Teratoid Rhabdoid Tumor. Our study showed that the K-B, although uncommon, it can be detected in non-PA tumors of various histogenesis and grading.

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