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BRAF; B-Raf proto-oncogene, serine/threonine kinase (7q34)

Gene Summary

Gene:BRAF; B-Raf proto-oncogene, serine/threonine kinase
Aliases: NS7, BRAF1, RAFB1, B-RAF1
Location:7q34
Summary:This gene encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene are associated with cardiofaciocutaneous syndrome, a disease characterized by heart defects, mental retardation and a distinctive facial appearance. Mutations in this gene have also been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung. A pseudogene, which is located on chromosome X, has been identified for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:serine/threonine-protein kinase B-raf
HPRD
Source:NCBI
Updated:12 July, 2014

Gene
Ontology:

What does this gene/protein do?
BRAF is implicated in:
- activation of MAPKK activity
- ATP binding
- calcium ion binding
- cellular response to calcium ion
- cytosol
- fibroblast growth factor receptor signaling pathway
- MAP kinase kinase kinase activity
- mitogen-activated protein kinase kinase binding
- negative regulation of apoptotic process
- negative regulation of neuron apoptotic process
- nerve growth factor receptor signaling pathway
- nucleus
- organ morphogenesis
- plasma membrane
- positive regulation of ERK1 and ERK2 cascade
- positive regulation of gene expression
- positive regulation of peptidyl-serine phosphorylation
- protein binding
- protein heterodimerization activity
- protein kinase activity
- protein phosphorylation
- protein serine/threonine kinase activity
- receptor signaling protein activity
- response to cAMP
- response to epidermal growth factor stimulus
- response to peptide hormone stimulus
- small GTPase mediated signal transduction
- synaptic transmission
Data from Gene Ontology via CGAP

Pathways:

What pathways are this gene/protein implicaed in?
- Dorso-ventral axis formation KEGG
- Focal adhesion KEGG
- MAPK signaling pathway KEGG
- mTOR signaling pathway KEGG
- Regulation of actin cytoskeleton KEGG
Data from KEGG and BioCarta [BIOCARTA terms] via CGAP

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 July 2014 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.

  • Quality Assurance, Health Care
  • Ubiquitination
  • DNA Methylation
  • Papillary Carcinoma
  • Epidermal Growth Factor Receptor
  • X-Ray Computed Tomography
  • Proto-Oncogene Proteins c-kit
  • Thyroidectomy
  • Pharmacogenetics
  • raf Kinases
  • Non-Hodgkin Lymphoma
  • GTP Phosphohydrolases
  • Drug Resistance
  • Sirolimus
  • Sequence Analysis, RNA
  • Neoplasm Metastasis
  • Mutation
  • Microsatellite Instability
  • Melanoma
  • Recurrence
  • Cancer DNA
  • Tumor Microenvironment
  • Rectum
  • BRAF
  • Membrane Proteins
  • Sulfonamides
  • Phosphatidylinositol 3-Kinases
  • Thyroid Cancer
  • Oncogenes
  • Protein Kinase Inhibitors
  • Immunohistochemistry
  • Cancer Gene Expression Regulation
  • DNA Mutational Analysis
  • Bowel Cancer
  • Lung Cancer
  • Chromosome 7
  • Carcinoma
  • Molecular Targeted Therapy
  • Staging
  • Antineoplastic Agents
  • Disease-Free Survival
  • Indoles
  • Proto-Oncogene Proteins
Tag cloud generated 12 July, 2014 using data from PubMed, MeSH and CancerIndex

Notable

BRAF and Melanoma

Related Publications (1188)

BRAF and Bowel Cancer

Related Publications (965)

BRAF and Thyroid Cancer

Related Publications (680)

BRAF and Lung Cancer

Related Publications (148)

BRAF and Non-Hodgkin's Lymphoma

Related Publications (15)

Related Links

Latest Publications: BRAF (cancer-related)

Kris MG, Johnson BE, Berry LD, et al.
Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.
JAMA. 2014; 311(19):1998-2006 [PubMed] Related Publications
IMPORTANCE: Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
OBJECTIVES: To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival.
DESIGN, SETTING, AND PARTICIPANTS: From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival.
INTERVENTIONS: Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies.
MAIN OUTCOMES AND MEASURES: Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival.
RESULTS: From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006).
CONCLUSIONS AND RELEVANCE: Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01014286.

Related: Lung Cancer


Sideris M, Papagrigoriadis S
Molecular biomarkers and classification models in the evaluation of the prognosis of colorectal cancer.
Anticancer Res. 2014; 34(5):2061-8 [PubMed] Related Publications
Colorectal cancer (CRC) is the second leading cause of cancer-related death. Despite the progress that has been made towards the identification of the molecular mechanisms involved in CRC, currently there are many unclear points. The current opinion is that microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) seem to play a significant role. MSI is related to point mutations in defect mismatch repair system of DNA. There are two well-established MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L or MSS). CIN refers to a different cellular event which originates from the presence of an abnormal chromosome complement or number. CIMP is the third most commonly involved event, and is defined by widespread methylation of CpG islands of suppressor promoters, with two phenotypes: CIMP-high and CIMP-low which interact with MSI or CIN status V-raf murine sarcoma viral oncogene homolog B (BRAF) is a serine-threonine protein kinase that acts as a downstream effector of the Kirsten rat sarcoma viral oncogene homolog (KRAS) pathway. Various studies have revealed that BRAF V600E mutations appear to be a valid indicator of poor prognosis. KRAS is a proto- oncogene which encodes a GTP-ase involved in cellular response to extracellular stimuli. Its prognostic value is still controversial. However, wild-type KRAS is associated with better response to Endothelial Growth Factor Receptor inhibitors combined with standard chemotherapy. Loss of Heterozygosity, especially involving 18q, is a well-known potential mechanism for tumorigenesis that has been studied in CRC. Vascular endothelial growth factor is a pro-angiogenic factor linked with the aggressiveness of CRC. Emerging data show that cycloxygenase 2 overexpression is significantly associated with worse outcomes in CRC. Recent studies highlight mi-croRNAs as promising prognostic biomarkers. More specifically, the down-regulation of miR-451, miR-625, miR-29c, miR-126, miR-129 and miR133 is purported to be a poor prognostic factor, while miR-224 was overexpressed in CRC.

Related: Colorectal (Bowel) Cancer


Gomes CC, Diniz MG, Gomez RS
Progress towards personalized medicine for ameloblastoma.
J Pathol. 2014; 232(5):488-91 [PubMed] Related Publications
Ameloblastoma is a locally infiltrative benign odontogenic neoplasm. Tumours may be large, destructive and recurrent, requiring radical surgery with associated facial deformity and morbidity. The molecular pathogenesis of this tumour has been unclear, retarding the development of non-invasive gene-targeted therapies. In a recent paper in this journal, Kurppa et al. [4] showed that EGFR-targeted therapy blocked cell proliferation in an ameloblastoma primary cell culture. That this therapy was not effective in another primary cell culture led to the discovery of the oncogenic BRAF V600E mutation in a high proportion (63%) of ameloblastoma samples. By defining two separate pathways, both of which can be specifically targeted, these findings are an important step towards personalized medicine of ameloblastoma. We discuss the findings in the broader context of ameloblastoma, as well as the effects of tumour microenvironment and molecular heterogeneity that need to be taken into account when considering the use of personalized therapies based on specific genetic mutations in individual patients.


McFadden DG, Vernon A, Santiago PM, et al.
p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer.
Proc Natl Acad Sci U S A. 2014; 111(16):E1600-9 [PubMed] Article available free on PMC after 22/10/2014 Related Publications
Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF-mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf(V600E) mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.

Related: Thyroid Cancer TP53


Serizawa M, Koh Y, Kenmotsu H, et al.
Assessment of mutational profile of Japanese lung adenocarcinoma patients by multitarget assays: a prospective, single-institute study.
Cancer. 2014; 120(10):1471-81 [PubMed] Related Publications
BACKGROUND: Integration of mutational profiling to identify driver genetic alterations in a clinical setting is necessary to facilitate personalized lung cancer medicine. A tumor genotyping panel was developed and the Shizuoka Lung Cancer Mutation Study was initiated as a prospective tumor genotyping study. This study reports the frequency of driver genetic alterations in Japanese lung adenocarcinoma patients, and clinicopathologic correlations with each genotype.
METHODS: Between July 2011 and January 2013, 411 lung adenocarcinoma patients admitted to the Shizuoka Cancer Center were included in this study with their written informed consent. Surgically resected tissues, tumor biopsies, and/or body cavity fluids were collected and tested for 23 hotspot sites of driver mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN, and HER2), gene amplifications in 5 genes (EGFR, MET, PIK3CA, FGFR1, and FGFR2), and ALK, ROS1, and RET fusions.
RESULTS: Genetic alterations were detected in 54.3% (223 of 411) of all patients. The most common genetic alterations detected in this study were EGFR mutations (35.0%) followed by KRAS mutations (8.5%) and ALK fusions (5.0%). Concurrent genetic alterations were detected in 22 patients (5.4%), and EGFR mutations were observed in 16 patients as the most common partner for concurrent genetic alteration. Significantly more concurrent genetic alterations were observed in older patients.
CONCLUSIONS: This is one of the largest reports of a prospective tumor genotyping study on Japanese patients with adenocarcinoma. These data suggest that mutational profiling data using a multimutational testing platform would be valuable for expanding the range of molecular-targeted therapeutics in lung cancer.

Related: Lung Cancer KRAS gene EGFR


Iwamoto S, Hazama S, Kato T, et al.
Multicenter phase II study of second-line cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type metastatic colorectal cancer: the FLIER study.
Anticancer Res. 2014; 34(4):1967-73 [PubMed] Related Publications
BACKGROUND: This study was the first multicenter phase II study of cetuximab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI) in KRAS wild-type mCRC as a second-line treatment in Japan including BRAF and PIK3CA genotyping.
PATIENTS AND METHODS: Tumors of 112 pre-registered patients were genotyped for KRAS, BRAF, and PIK3CA. The primary study end-point was response rate, and secondary end-points were progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: Sixty-seven patients (59.8%) were EGFR-positive and KRAS wild-type. The mean age of the enrolled patients (n=60) was 62.6 years (range=37-82 years). The response rate was 31.7% and stable disease was observed in 53.3%. No objective response was observed in patients with BRAF or PIK3CA mutations. The median PFS and OS were 7.4 and 18.2 months, respectively. Grade-3/4 adverse events were leucopenia (26.7%), neutropenia (43.3%), paronychia (10.0%), fissure (10.0%) and acne-like rash (5.0%).
CONCLUSION: Second-line cetuximab plus FOLFIRI was effective and well-tolerated.

Related: Colorectal (Bowel) Cancer Fluorouracil Leucovorin Irinotecan Cetuximab (Erbitux)


Sun C, Wang L, Huang S, et al.
Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.
Nature. 2014; 508(7494):118-22 [PubMed] Related Publications
Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.

Related: Melanoma Signal Transduction Vemurafenib (Zelboraf)


Bozok Cetintas V, Tezcanli Kaymaz B, Aktug H, et al.
Capsaicin induced apoptosis and gene expression dysregulation of human acute lymphoblastic leukemia CCRF-CEM cells.
J BUON. 2014 Jan-Mar; 19(1):183-90 [PubMed] Related Publications
PURPOSE: Capsaicin, an ingredient of red chili pepper, has possible tumorigenicity/genotoxicity properties. We aimed to determine the effects of capsaicin on the proliferation and gene expression profiles of acute lymphoblastic leukemia (ALL) CCRF-CEM cell line.
METHODS: Cell viability and IC50 dose was determined by WST cytotoxicity assay. qRT-PCR, immunohistochemical staining and western blot methods were used to determine target genes' expression levels. Apoptosis was evaluated by measuring the caspase-3 activity.
RESULTS: Capsaicin inhibited the proliferation of CCRFCEM cells in a dose-dependent manner. Increased mRNA expressions of caspase gene family members, activated caspase-3 and decreased mRNA and protein expression of BCL-2 gene indicated apoptotic response to capsaicin. Moreover capsaicin treatment suppressed significantly the expression of the key cell signaling pathways of KRAS, AKT, GAB2, PTPN11, BRAF, INPP5D, MAPK7.
CONCLUSION: Capsaicin induces apoptosis in CCRF-CEM cells and this response is associated with downregulation of cell signaling pathways.

Related: Apoptosis Acute Lymphocytic Leukemia (ALL) Signal Transduction


Etchevers HC
Hiding in plain sight: molecular genetics applied to giant congenital melanocytic nevi.
J Invest Dermatol. 2014; 134(4):879-82 [PubMed] Related Publications
Large and giant congenital melanocytic nevi are rare malformations that offer surprising insight into prenatal and postnatal acquisition of nevi of any size, central and peripheral nervous system development, and melanomagenesis. In this issue, Charbel et al. demonstrate the use of highly sensitive detection techniques for recurrent but difficult-to-detect mutations in NRAS and BRAF. It is now possible to systematically add a molecular qualifier to distinguish lesions that had once been considered to be equivalent based on the single visual parameter of size. These findings help to elucidate the pathophysiology of congenital melanocytic nevi and their predisposition to malignancy.

Related: NRAS gene


Jang GH, Lee M
BH3-mimetic gossypol-induced autophagic cell death in mutant BRAF melanoma cells with high expression of p21Cip¹.).
Life Sci. 2014; 102(1):41-8 [PubMed] Related Publications
AIMS: The aim of the present study was to identify the potential therapeutic effects of BH3-mimetic gossypol on melanoma cells with acquired resistance to BRAF inhibitors.
MAIN METHODS: The IC50 values of gossypol were determined using MTT assays in three melanoma cell lines with different resistances to BRAF inhibitor. The effects of gossypol on three melanoma cell lines were further examined by immunoblotting analysis, cell cycle analysis, flow cytometric apoptotic assay and autophagy assay. The functional role of autophagy in gossypol-induced growth inhibition was investigated using siRNA-mediated knockdown of Beclin-1.
KEY FINDINGS: Gossypol retained its efficacy in BRAF-V600E melanoma clones with acquired resistance to BRAF inhibitors through a mechanism independent of MEK-ERK inhibition. Gossypol caused G2/M arrest in both BRAF mutant A375P and A375P/Mdr cells with high expression of p21(Cip1), regardless of their drug resistance. Interestingly, we determined that the lack of gossypol-induced mitotic arrest in BRAF-WT-harboring SK-MEL-2 cells was associated with a low level of p21(Cip1) expression. In addition, gossypol preferentially induced autophagy and apoptosis in the gossypol-sensitive cells and not in the gossypol-resistant SK-MEL-2 cells. In particular, alleviation of autophagy by knockdown of Beclin-1 partially caused a resistance to gossypol-induced cell cycle arrest at G2/M in BRAF-V600E cells with a concomitant decreased induction of apoptosis.
SIGNIFICANCE: Taken together, these results suggest that gossypol may exhibit potential for the treatment of BRAF inhibitor-resistant tumors, but a functional p21(Cip1) is a prerequisite for a positive response to its clinical application.

Related: Apoptosis CDKN1A Melanoma


Pai RK, Shadrach BL, Carver P, et al.
Immunohistochemistry for annexin A10 can distinguish sporadic from Lynch syndrome-associated microsatellite-unstable colorectal carcinoma.
Am J Surg Pathol. 2014; 38(4):518-25 [PubMed] Related Publications
Differentiating sporadic microsatellite-unstable colorectal carcinoma due to MLH1 promoter hypermethylation from Lynch syndrome (LS)-associated tumors due to mutations in mismatch-repair proteins is time consuming, cost intensive, and requires advanced laboratory testing. A mutation in BRAF has been shown to be highly specific for sporadic tumors; however, a significant proportion of sporadic microsatellite-unstable tumors lack BRAF mutations. MLH1 promoter methylation analysis is subsequently used to differentiate LS and sporadic tumors, but both tests require specialized laboratories and are costly. Through previous gene expression profiling of serrated polyps, we identified annexin A10 as a protein highly expressed in sessile serrated adenomas/polyps. As these polyps give rise to the majority of sporadic microsatellite-unstable tumors, we evaluated the ability of annexin A10 expression to discriminate between LS and sporadic tumors. A marked increase in annexin A10 mRNA was observed in sporadic microsatellite-unstable tumors compared with LS tumors (378-fold increase, P<0.001). Using immunohistochemistry, annexin A10 was expressed in 23/53 (43%) BRAF-mutated and 9/22 (41%) BRAF wild-type sporadic tumors. In contrast, only 3/56 (5%) LS tumors were positive for annexin A10 (P<0.0001). One patient had a deleterious MSH2 mutation, and another had a variant of uncertain significance in MSH6. These 2 tumors could be easily distinguished from sporadic tumors using mismatch-repair protein immunohistochemistry. Only 1/28 (4%) LS tumors with loss of MLH1 was positive for annexin A10. This patient did not have a deleterious MLH1 mutation but rather germline promoter hypermethylation of MLH1. On the basis of these results, immunohistochemistry for annexin A10 may be a useful marker to distinguish sporadic from LS-associated microsatellite-unstable colon cancer.

Related: Colorectal (Bowel) Cancer


Razis E, Pentheroudakis G, Rigakos G, et al.
EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab.
J Cancer Res Clin Oncol. 2014; 140(5):737-48 [PubMed] Related Publications
INTRODUCTION: Cetuximab is a monoclonal epidermal growth factor receptor (EGFR)-targeting antibody, used in the treatment of colon cancer. KRAS mutation status is strongly predictive of cetuximab efficacy, but more predictive factors are needed for better patient selection. PTEN is a downstream inhibitor of the EGFR pathway and has been evaluated as a predictive factor of cetuximab efficacy in colorectal cancer.
PATIENTS AND METHODS: Formalin-fixed paraffin-embedded tumor tissue samples were collected from 226 patients with advanced or metastatic colorectal cancer that had been treated with cetuximab. Clinical information was collected retrospectively from the patients' medical records. After central evaluation, 147 cases with adequate material were eligible for further evaluation. EGFR and PTEN status was evaluated with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Data were associated with cetuximab treatment outcome. Additional analysis was performed with previously published data on PIK3CA, BRAF and KRAS mutation status and EGFR ligand amphiregulin (AREG) and epiregulin intratumoral mRNA expression levels. PIK3CA mutation status and PTEN protein expression were also analyzed as a single complex parameter, to evaluate the predictive value of PI3K/PTEN axis dysfunction as one entity.
RESULTS: Analysis showed a borderline association of overall response rate (ORR) and time to progression (TTP) with EGFR protein overexpression by IHC (p = 0.059 and p = 0.057, respectively) and a positive association of EGFR gain by FISH (found in only five cases) with longer TTP (p = 0.026). No association was found between ORR or TTP and PTEN IHC or FISH status. Comparative analysis with previously published data showed that PTEN protein expression is associated with longer TTP in patients with wild-type (WT) KRAS (p = 0.036) and especially in the ones with elevated AREG levels (p = 0.046), as well as in patients with both KRAS and BRAF WT (p = 0.019). Patients with both PIK3CA WT and PTEN protein expression had significantly longer TTP (p = 0.010) versus all others, in the absence of BRAF and KRAS mutations, a finding which persisted in the KRAS WT/AREG high subgroup (p = 0.046).
CONCLUSIONS: In this cetuximab-treated colorectal cancer population, EGFR gain was associated with better outcome and PTEN protein expression with longer TTP in KRAS WT, KRAS WT/AREG high and KRAS/BRAF WT subpopulations. Cetuximab efficacy is greater with intact and activated EGFR signaling, without activating mutations of KRAS/BRAF and in the presence of preserved PTEN inhibitory activity upon the PI3K/AKT pathway. These results reflect a solid biological rationale and warrant further evaluation of the predictive role of PTEN in prospective studies.

Related: Colorectal (Bowel) Cancer PTEN KRAS gene EGFR Cetuximab (Erbitux)


Cerne JZ, Hartig SM, Hamilton MP, et al.
Protein kinase C inhibitors sensitize GNAQ mutant uveal melanoma cells to ionizing radiation.
Invest Ophthalmol Vis Sci. 2014; 55(4):2130-9 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
PURPOSE: Uveal melanoma (UM) tumors require large doses of radiation therapy (RT) to achieve tumor ablation, which frequently results in damage to adjacent normal tissues, leading to vision-threatening complications. Approximately 50% of UM patients present with activating somatic mutations in the gene encoding for G protein αq-subunit (GNAQ), which lead to constitutive activation of downstream pathways, including protein kinase C (PKC). In this study, we investigated the impact of small-molecule PKC inhibitors bisindolylmaleimide I (BIM) and sotrastaurin (AEB071), combined with ionizing radiation (IR), on survival in melanoma cell lines.
METHODS: Cellular radiosensitivity was determined by using a combination of proliferation, viability, and clonogenic assays. Cell-cycle effects were measured by flow cytometry. Transcriptomic and proteomic profiling were performed by quantitative real-time PCR, reverse-phase protein array analysis, and immunofluorescence.
RESULTS: We found that the PKC inhibitors combined with IR significantly decreased the viability, proliferation, and clonogenic potential of GNAQ(mt), but not GNAQ(wt)/BRAF(mt) cells, compared with IR alone. Combined treatment increased the antiproliferative and proapoptotic effects of IR in GNAQ(mt) cells through delayed DNA-damage resolution and enhanced induction of proteins involved in cell-cycle arrest, cell-growth arrest, and apoptosis.
CONCLUSIONS: Our preclinical results suggest that combined modality treatment may allow for reductions in the total RT dose and/or fraction size, which may lead to better functional organ preservation in the treatment of primary GNAQ(mt) UM. These findings suggest future clinical trials combining PKC inhibitors with RT in GNAQ(mt) UM warrant consideration.

Related: Apoptosis Melanoma Ocular Melanoma IntraOcular Melanoma


de Macedo MP, de Lima LG, Begnami MD, et al.
KRAS insertions in colorectal cancer: what do we know about unusual KRAS mutations?
Exp Mol Pathol. 2014; 96(2):257-60 [PubMed] Related Publications
INTRODUCTION: KRAS mutations are negative predictors of the response to anti-EGFR therapy in colorectal carcinomas (CRCs). Point mutations in codons 12, 13, and 61 are the most common KRAS mutations in CRC. There are few reports on insertions in KRAS, and little is known about its ability to activate the RAS pathway. The scarcity of data regarding insertion frequencies and nucleotide additions in KRAS impedes the management of patients with such mutations. We present data on KRAS insertions in CRC and discuss a case.
MATERIALS AND METHODS: Pyrosequencing and Sanger sequencing were performed to identify KRAS and BRAF mutations in paraffin-embedded samples of CRC. Expression of mismatch repair proteins was examined by immunohistochemistry.
RESULTS: We detected a GGT insertion between codons 12 and 13 (c.36_37insGGT;p.G12_G13insG) in a CRC patient. We found that insertions in KRAS is very rare in CRC and that the most frequent type of insertion is c.36_37insGGT.
CONCLUSIONS: KRAS gene insertions represent a diagnostic and clinical challenge due to the difficult and unusual pyrosequencing findings and the lack of information regarding its clinical impact.

Related: Colorectal (Bowel) Cancer KRAS gene


Hyeon J, Ahn S, Shin JH, Oh YL
The prediction of malignant risk in the category "atypia of undetermined significance/follicular lesion of undetermined significance" of the Bethesda System for Reporting Thyroid Cytopathology using subcategorization and BRAF mutation results.
Cancer Cytopathol. 2014; 122(5):368-76 [PubMed] Related Publications
BACKGROUND: The "atypia of undetermined significance/follicular lesion of undetermined significance" (AUS/FLUS) category in the Bethesda System for Reporting Thyroid Cytopathology is a heterogeneous category of cases that are not clearly benign or malignant.
METHODS: We conducted an analysis of cytologic and histologic evaluations of thyroid nodules that had been interpreted as AUS/FLUS on fine-needle aspiration (FNA) at a single institution from April 2011 to April 2012. Those cases were classified into 2 subgroups according to the predominance of nuclear atypia (AUS) or microfollicular architecture (FLUS). In addition, for a number of these cases, BRAF gene mutation analyses were performed.
RESULTS: Of 6402 thyroid FNAs performed, 431 cases were diagnosed as AUS and 120 as FLUS. Follow-up cytologic or histologic outcome data were available for 315 AUS cases and 73 FLUS cases. Among AUS cases, 52.7% were malignant on repeat FNA or histologic diagnosis. In contrast, for FLUS, 6.8% were malignant on repeat FNA or histologic diagnosis. Among AUS/FLUS cases, 147 had adequate BRAF mutation analysis, which accompanied the histologic diagnosis. BRAF mutations were found in 87 AUS cases, 86 of which were papillary carcinoma. In contrast, there was only 1 case of BRAF mutation in FLUS. Correlating molecular results with histologic outcome revealed a 98.9% cancer probability for AUS cases with BRAF mutation.
CONCLUSIONS: The AUS subcategory indicates a higher risk of malignancy than the FLUS subcategory. Furthermore, BRAF molecular testing is helpful in stratifying the malignant risk of AUS cases into high-risk and low-risk groups.

Related: Thyroid Cancer


Qiu Y, Fu X, Zhang W, et al.
Prevalence and molecular characterisation of the sessile serrated adenoma in a subset of the Chinese population.
J Clin Pathol. 2014; 67(6):491-8 [PubMed] Related Publications
AIMS: The incidence and mortality rates from right-sided colorectal cancers (CRCs) have not decreased in recent years. It is very likely that a significant proportion of these cancers evolve from undetected sessile serrated adenomas (SSAs). The prevalence and molecular features of the SSAs in the Chinese population have seldom been investigated.
METHODS: We retrospectively reviewed the colonoscopy database and pathology archives in our medical centre. Adenomatous polyposis coli (APC) and β-catenin expressions were examined in 28 right hyperplastic polyps (RHPs) and 21 SSAs by immunohistochemical staining. The mutations of BRAF, KRAS, APC and β-CATENIN were analysed by direct sequencing. The methylation status of APC promoter in these polyps was analysed by methylation-specific PCR and bisulfite sequencing. Samples of left hyperplastic polyps, traditional adenomas and CRC were used as controls.
RESULTS: SSAs accounted for 4.9% of serrated polyps and 1.0% of all colorectal polyps. BRAF((V600E)) mutations were found in 14.3% of SSAs and 7.1% of RHPs. Nuclear accumulation of β-catenin was seen in 28.6% of SSAs and 17.9% of RHPs. APC mutations were detected in 57.1% of SSAs and 67.9% of RHPs. APC methylation was detected in 14.3% of RHPs and 23.8% of SSAs.
CONCLUSIONS: The prevalence of SSAs in a subset of the Chinese population is much lower than that in the Western population. BRAF((V600E)) mutation is not a frequent event in right colon serrated polyps in a subset of the Chinese population. APC mutation is possibly the main cause for the Wnt signalling activation in right colon serrated polyps.

Related: Colorectal (Bowel) Cancer KRAS gene


Imielinski M, Greulich H, Kaplan B, et al.
Oncogenic and sorafenib-sensitive ARAF mutations in lung adenocarcinoma.
J Clin Invest. 2014; 124(4):1582-6 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Targeted cancer therapies often induce "outlier" responses in molecularly defined patient subsets. One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a near-complete clinical and radiographic remission for 5 years. Whole-genome sequencing and RNA sequencing of primary tumor and normal samples from this patient identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutations were shown to transform immortalized human airway epithelial cells in a sorafenib-sensitive manner. These results suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

Related: Lung Cancer Sorafenib (Nexavar)


Ma XH, Piao SF, Dey S, et al.
Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma.
J Clin Invest. 2014; 124(3):1406-17 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAF(V600E) melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAF(V600E) melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.

Related: Melanoma Vemurafenib (Zelboraf)


Berge EM, Doebele RC
Targeted therapies in non-small cell lung cancer: emerging oncogene targets following the success of epidermal growth factor receptor.
Semin Oncol. 2014; 41(1):110-25 [PubMed] Related Publications
The diagnostic testing, treatment and prognosis of non-small cell lung cancer (NSCLC) has undergone a paradigm shift since the discovery of sensitizing mutations in the epidermal growth factor receptor (EGFR) gene in a subset of NSCLC patients. Several additional oncogenic mutations, including gene fusions and amplifications, have since been discovered, with a number of drugs that target each specific oncogene. This review focuses on oncogenes in NSCLC other than EGFR and their companion "targeted therapies." Particular emphasis is placed on the role of ALK, ROS1, RET, MET, BRAF, and HER2 in NSCLC.

Related: Non-Small Cell Lung Cancer Lung Cancer EGFR


Krayem M, Journe F, Wiedig M, et al.
Prominent role of cyclic adenosine monophosphate signalling pathway in the sensitivity of (WT)BRAF/(WT)NRAS melanoma cells to vemurafenib.
Eur J Cancer. 2014; 50(7):1310-20 [PubMed] Related Publications
Vemurafenib improves survival in patients with melanoma bearing the (V600E)BRAF mutation, but it did not show any benefit in clinical trials focusing on wild type tumours while it may well inhibit (WT)BRAF considering the dosage used and the bioavailability of the drug. As tumours may contain a mixture of mutant and wild type BRAF cells and this has been also put forward as a resistance mechanism, we aimed to evaluate the sensitivity/resistance of six, randomly selected, (WT)BRAF/(WT)NRAS lines to vemurafenib and found four sensitive. The sensitivity to the drug was accompanied by a potent inhibition of both phospho-ERK and phospho-AKT, and a significant induction of apoptosis while absent in lines with intrinsic or acquired resistance. Phospho-CRAF expression was low in all sensitive lines and high in resistant ones, and MEK inhibition can effectively potentiate the drug effect. A possible explanation for CRAF modulation is cyclic adenosine monophosphate (cAMP), a mediator of melanocortin receptor 1 (MC1R) signalling, since it can actually inhibit CRAF. Indeed, we measured cAMP and found that all four sensitive lines contained significantly higher constitutive cAMP levels than the resistant ones. Consequently, vemurafenib and cAMP stimulator combination resulted in a substantial synergistic effect in lines with both intrinsic and acquired resistance but only restricted to those where cAMP was effectively increased. The use of a cAMP agonist overcame such restriction. In conclusion, we report that (WT)BRAF/(WT)NRAS melanoma lines with low phospho-CRAF and high cAMP levels may be sensitive to vemurafenib and that CRAF inhibition through cAMP stimulation may overcome the resistance to the drug.

Related: Apoptosis Melanoma Signal Transduction Vemurafenib (Zelboraf) NRAS gene


Sale MJ, Cook SJ
The increase in BIK expression following ERK1/2 pathway inhibition is a consequence of G₁ cell-cycle arrest and not a direct effect on BIK protein stability.
Biochem J. 2014; 459(3):513-24 [PubMed] Related Publications
BIK (BCL2-interacting killer) is a pro-apoptotic BH3 (BCL2 homology domain 3)-only protein and a member of the BCL2 protein family. It was proposed recently that BIK abundance is controlled by ERK1/2 (extracellular-signal-regulated kinase 1/2)-catalysed phosphorylation, which targets the protein for proteasome-dependent destruction. In the present study, we examined ERK1/2-dependent regulation of BIK, drawing comparisons with BIM(EL) (BCL2-interacting mediator of cell death; extra long), a well-known target of ERK1/2. In many ERK1/2-dependent tumour cell lines, inhibition of BRAF(V600E) (v-raf murine sarcoma viral oncogene homologue B1, V600E mutation) or MEK1/2 (mitogen-activated protein kinase/ERK kinase 1/2) had very little effect on BIK expression, whereas BIM(EL) was strongly up-regulated. In some cell lines we observed a modest increase in BIK expression; however, this was not apparent until ~16 h or later, whereas BIM(EL) expression increased rapidly within a few hours. Although BIK was degraded by the proteasome, we found no evidence that this was regulated by ERK1/2 signalling. Rather, the delayed increase in BIK expression was prevented by actinomycin D, and was accompanied by increases in BIK mRNA. Finally, the delayed increase in BIK expression following ERK1/2 inhibition was phenocopied by a highly selective CDK4/6 (cyclin-dependent kinases 4 and 6) inhibitor, which caused a strong G₁ cell-cycle arrest without inhibiting ERK1/2 signalling. In contrast, BIM(EL) expression was induced by ERK1/2 inhibition, but not by CDK4/6 inhibition. We conclude that BIK expression is not subject to direct regulation by the ERK1/2 pathway; rather, we propose that BIK expression is cell-cycle-dependent and increases as a consequence of the G₁ cell-cycle arrest which results from inhibition of ERK1/2 signalling.

Related: Cancer Prevention and Risk Reduction BIK


Gala MK, Mizukami Y, Le LP, et al.
Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.
Gastroenterology. 2014; 146(2):520-9 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
BACKGROUND & AIMS: Little is known about the genetic factors that contribute to the development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells. Progression to serrated neoplasia requires cells to escape OIS via inactivation of tumor suppressor pathways. We investigated whether subjects with multiple SSAs carry germline loss-of function mutations (nonsense and splice site) in genes that regulate OIS: the p16-Rb and ATM-ATR DNA damage response pathways.
METHODS: Through a bioinformatic analysis of the literature, we identified a set of genes that function at the main nodes of the p16-Rb and ATM-ATR DNA damage response pathways. We performed whole-exome sequencing of 20 unrelated subjects with multiple SSAs; most had features of serrated polyposis. We compared sequences with those from 4300 subjects matched for ethnicity (controls). We also used an integrative genomics approach to identify additional genes involved in senescence mechanisms.
RESULTS: We identified mutations in genes that regulate senescence (ATM, PIF1, TELO2,XAF1, and RBL1) in 5 of 20 subjects with multiple SSAs (odds ratio, 3.0; 95% confidence interval, 0.9–8.9; P =.04). In 2 subjects,we found nonsense mutations in RNF43, indicating that it is also associated with multiple serrated polyps (odds ratio, 460; 95% confidence interval, 23.1–16,384; P = 6.8 x 10(-5)). In knockdown experiments with pancreatic duct cells exposed to UV light, RNF43 appeared to function as a regulator of ATMATRDNA damage response.
CONCLUSIONS: We associated germline loss-of-function variants in genes that regulate senescence pathways with the development of multiple SSAs.We identified RNF43 as a regulator of the DNA damage response and associated nonsense variants in this gene with a high risk of developing SSAs.

Related: RBL1 retinoblastoma-like 1 (p107) KRAS gene


Kim HK, Lee HY, Choi YL, et al.
Assessment of intratumoral heterogeneity of oncogenic driver mutations in surgically-resected lung adenocarcinoma: implications of percutaneous biopsy-based molecular assay for target-directed therapy.
Anticancer Res. 2014; 34(2):707-14 [PubMed] Related Publications
AIM: The present study investigated whether there is intratumoral heterogeneity of oncogenic driver mutations within surgically-resected tumors and between surgical specimens and percutaneous biopsy samples.
PATIENTS AND METHODS: Thirty-four patients who underwent surgery for lung adenocarcinoma were studied. We obtained four to five snap-frozen samples from each surgical specimen. Mutational analyses of epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit-alpha (PIK3CA) genes were performed and then compared in multiple surgical specimens and between surgical and percutaneous biopsy samples.
RESULTS: EGFR and KRAS mutations were detected in 19 and 2 patients, respectively. Multiple surgical samples from different areas of the tumor had the same mutation genotype in all cases except for one. The 14 biopsy specimens had the same mutational profiles as the corresponding surgical specimens.
CONCLUSION: Heterogeneous distributions of oncogenic driver mutations were not found in surgically-resected lung adenocarcinoma. Small tumor specimens obtained with percutaneous biopsy were suitable for EGFR analyses, thus providing critical information for personalized therapy.

Related: Lung Cancer KRAS gene EGFR


Messuti I, Corvisieri S, Bardesono F, et al.
Impact of pregnancy on prognosis of differentiated thyroid cancer: clinical and molecular features.
Eur J Endocrinol. 2014; 170(5):659-66 [PubMed] Related Publications
OBJECTIVE: Differentiated thyroid cancer (DTC) commonly occurs in women of child-bearing age and represents the second most frequent tumor diagnosed during pregnancy only behind breast cancer. It is possible that associated physiological changes could favor tumor development and growth. However, few data are available about the outcome of DTC related to pregnancy, leading to conflicting results.
METHODS: Among the study population, 340 patients with DTC <45 years old were retrospectively studied. Patients were divided into three groups according to the time of tumor diagnosis in respect of pregnancy. Group 1, diagnosis of DTC at least 2 years after delivery; group 2, diagnosis during pregnancy or within the second year after delivery; and group 3, nulliparous patients at the time of diagnosis. We evaluated clinical outcome and immunohistochemical expression of estrogen receptor α (ERα), ERβ, progesterone receptor, and aromatase. We also analyzed the gene expression of NIS (SLC5A5) and the prevalence of BRAF(V600E) mutations.
RESULTS: Persistence/recurrence of disease was significantly higher in group 2 patients than control groups (P=0.023). No significant differences were observed in other clinical parameters. Furthermore, no differences among the groups were recorded about ER pattern, NIS expression, and BRAF mutations.
CONCLUSIONS: Persistence/recurrence of DTC is significantly higher in pregnant patients, suggesting that pregnancy could really exert a negative prognostic role in patients with DTC. The underlying mechanisms are not yet clarified and further studies are required. Our results suggest that a more careful follow-up is needed when diagnosis of DTC occurs during pregnancy or shortly after.

Related: Breast cancer in pregnancy Thyroid Cancer


Li S, Mattar P, Dixit R, et al.
RAS/ERK signaling controls proneural genetic programs in cortical development and gliomagenesis.
J Neurosci. 2014; 34(6):2169-90 [PubMed] Related Publications
Neural cell fate specification is well understood in the embryonic cerebral cortex, where the proneural genes Neurog2 and Ascl1 are key cell fate determinants. What is less well understood is how cellular diversity is generated in brain tumors. Gliomas and glioneuronal tumors, which are often localized in the cerebrum, are both characterized by a neoplastic glial component, but glioneuronal tumors also have an intermixed neuronal component. A core abnormality in both tumor groups is overactive RAS/ERK signaling, a pro-proliferative signal whose contributions to cell differentiation in oncogenesis are largely unexplored. We found that RAS/ERK activation levels differ in two distinct human tumors associated with constitutively active BRAF. Pilocytic astrocytomas, which contain abnormal glial cells, have higher ERK activation levels than gangliogliomas, which contain abnormal neuronal and glial cells. Using in vivo gain of function and loss of function in the mouse embryonic neocortex, we found that RAS/ERK signals control a proneural genetic switch, inhibiting Neurog2 expression while inducing Ascl1, a competing lineage determinant. Furthermore, we found that RAS/ERK levels control Ascl1's fate specification properties in murine cortical progenitors--at higher RAS/ERK levels, Ascl1(+) progenitors are biased toward proliferative glial programs, initiating astrocytomas, while at moderate RAS/ERK levels, Ascl1 promotes GABAergic neuronal and less glial differentiation, generating glioneuronal tumors. Mechanistically, Ascl1 is phosphorylated by ERK, and ERK phosphoacceptor sites are necessary for Ascl1's GABAergic neuronal and gliogenic potential. RAS/ERK signaling thus acts as a rheostat to influence neural cell fate selection in both normal cortical development and gliomagenesis, controlling Neurog2-Ascl1 expression and Ascl1 function.


Russo AL, Borger DR, Szymonifka J, et al.
Mutational analysis and clinical correlation of metastatic colorectal cancer.
Cancer. 2014; 120(10):1482-90 [PubMed] Related Publications
BACKGROUND: Early identification of mutations may guide patients with metastatic colorectal cancer toward targeted therapies that may be life prolonging. The authors assessed tumor genotype correlations with clinical characteristics to determine whether mutational profiling can account for clinical similarities, differences, and outcomes.
METHODS: Under Institutional Review Board approval, 222 patients with metastatic colon adenocarcinoma (n = 158) and rectal adenocarcinoma (n = 64) who underwent clinical tumor genotyping were reviewed. Multiplexed tumor genotyping screened for >150 mutations across 15 commonly mutated cancer genes. The chi-square test was used to assess genotype frequency by tumor site and additional clinical characteristics. Cox multivariate analysis was used to assess the impact of genotype on overall survival.
RESULTS: Broad-based tumor genotyping revealed clinical and anatomic differences that could be linked to gene mutations. NRAS mutations were associated with rectal cancer versus colon cancer (12.5% vs 0.6%; P < .001) and with age ≥56 years (7% vs 0.9%; P = .02). Conversely, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations were associated with colon cancer (13% vs 3%; P = .024) and older age (15.8% vs 4.6%; P = .006). TP53 mutations were associated with rectal cancer (30% vs 18%; P = .048), younger age (14% vs 28.7%; P = .007), and men (26.4% vs 14%; P = .03). Lung metastases were associated with PIK3CA mutations (23% vs 8.7%; P = .004). Only mutations in BRAF were independently associated with decreased overall survival (hazard ratio, 2.4; 95% confidence interval, 1.09-5.27; P = .029).
CONCLUSIONS: The current study suggests that underlying molecular profiles can differ between colon and rectal cancers. Further investigation is warranted to assess whether the differences identified are important in determining the optimal treatment course for these patients.

Related: TP53 KRAS gene NRAS gene


Debunne H, Ceelen W
Mucinous differentiation in colorectal cancer: molecular, histological and clinical aspects.
Acta Chir Belg. 2013 Nov-Dec; 113(6):385-90 [PubMed] Related Publications
UNLABELLED: BACKGROUND : Mucinous colorectal carcinoma represents a subtype of colorectal carcinoma (CRC), which is characterized by abundant amount of extracellular mucin. We reviewed the molecular, histological and clinical aspects of mucinous CRC as compared to the non-mucinous type.
METHODS: A systematic web-based research was performed using Web of Knowledge. The combination of the Boolean search terms "COLO" AND "MUC" was used. The literature was searched until July 2013.
RESULTS: Patients with mucinous CRC have distinct clinical and pathological features. Mucinous CRC tends to occur in younger patients, are often seen in the proximal colon, are more diagnosed at an advanced stage and are more frequently associated with hereditary non-polyposis colorectal cancer (HNPCC) and young-age sporadic colorectal cancer. The prognostic significance of mucinous differentiation remains uncertain; some studies have shown a poor response to oxaliplatin and/or irinotecan based chemotherapy. Mucinous CRC is associated with a higher expression of MUC2 and MUC5AC, but a lower expression of MUC1. The differential expression of mucins has been related to altered risk of metastasis and death. Recently, mucins have been used as targets for molecular therapy and as a source of immune therapy. Mucinous differentiation is associated with other specific genetic and molecular features such as increased BRAF mutation rate and microsatellite instability.
CONCLUSION: Mucinous CRC is a distinct clinical, pathological, and molecular entity. The implications of mucinous differentiation for treatment response and outcome are not fully elucidated, but the available data suggest an adverse effect. The use of mucins as immunotargets may show therapeutic promise for mucinous CRC.

Related: Colorectal (Bowel) Cancer MUC1 gene MUC2


Kraus S, Nabiochtchikov I, Shapira S, Arber N
Recent advances in personalized colorectal cancer research.
Cancer Lett. 2014; 347(1):15-21 [PubMed] Related Publications
Colorectal cancer is one of the most prevalent cancers and a leading cause ofcancer-related death. It is also curable if detected early. The prognosis for metastatic colorectal cancer remains poor and resistance to chemotherapy is still a major obstacle in effective treatment. While many patients do not clinically benefit from chemotherapy, others experience adverse reactions resulting in dose modifications or treatment withdrawal, thereby reducing treatment efficacy. Researchefforts attempt to identify reliable biomarkers which will guide clinicians in decision making, while matching suitable therapeutic regimens. We here review currently known molecular biomarkers used for the personalized treatment of colorectal cancer.

Related: Colorectal (Bowel) Cancer Polymorphisms


Yazdan P, Cooper C, Sholl LM, et al.
Comparative analysis of atypical spitz tumors with heterozygous versus homozygous 9p21 deletions for clinical outcomes, histomorphology, BRAF mutation, and p16 expression.
Am J Surg Pathol. 2014; 38(5):638-45 [PubMed] Related Publications
Studies have shown that atypical Spitz tumors (ASTs) with homozygous deletions in 9p21 have worse prognosis than those without this finding. Conversely, numerous studies have shown that a range of other copy number aberrations including isolated 6q23 or 3p21 loss may be seen in ASTs without conferring higher risk for aggressive behavior. We studied 31 cases of ASTs with heterozygous 9p21 loss and hypothesize that heterozygous 9p21 loss in ASTs does not confer an increased risk for aggressive behavior. We compared clinical, histopathologic, and immunohistochemical features of 31 ASTs with heterozygous 9p21 deletions with 30 ASTs with homozygous 9p21 deletions. No ASTs with heterozygous 9p21 deletions resulted in distant metastasis. Severe cytologic atypia, a predominance of epithelioid cytomorphology and increased dermal mitotic activity were more frequent in ASTs with homozygous deletions versus ASTs with heterozygous deletions (P=0.0003, 0.0004, and 0.042, respectively). Expression of p16 and mutated BRAF proteins was also evaluated in 17 conventional (nonspitzoid) melanomas with homozygous 9p21 loss and the 2 groups of ASTs. Expression of p16 was retained in 67% of ASTs with heterozygous loss, whereas among ASTs with homozygous loss, 100% of cases had areas with complete loss of staining. Mutated BRAF protein expression was detected in 53% of conventional melanomas, in none of the ASTs with heterozygous loss, and in 1 AST with homozygous loss (P=0.0007 between homozygous ASTs and the conventional melanomas). Coexisting BRAF mutation and 9p21 deletion was more common in conventional melanomas than in ASTs with heterozygous or homozygous 9p21 deletion. BRAF mutation was highly uncommon among the ASTs.

Related: Chromosome 9 FISH Skin Cancer


Lee KH, Kim HS, Han BK, et al.
Incidence and predictive factors of inadequate fine-needle aspirates for BRAF(V600E) mutation analysis in thyroid nodules.
AJR Am J Roentgenol. 2014; 202(2):391-6 [PubMed] Related Publications
OBJECTIVE: BRAF(V600E) mutation (valine-to-glutamate substitution at residue 600 of the B-type Raf kinase gene) analysis from thyroid aspirates is increasingly used as a prognostic or diagnostic marker. However, it is limited under some conditions. The purpose of this study was to assess the incidence and predictive factors of thyroid nodules with specimens inadequate for BRAF(V600E) mutation analysis.
MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive patients who underwent ultrasound-guided fine-needle aspiration (FNA) and molecular testing of aspiration specimens. Patients who had inadequate specimens in both allele-specific polymerase chain reaction and direct DNA-sequencing methods were selected. Univariate and multivariate logistic regression analyses were performed to identify predictive factors of specimens inadequate for molecular tests.
RESULTS: Specimens inadequate for BRAF(V600E) mutation analysis were seen in 168 of 7001 (2.4%) patients. Factors, including patient age and sex, nodule size, ultrasound diagnosis, the presence of calcification, and cystic changes within thyroid nodules, were not significant predictors of inadequate mutation analysis. Oval-to-round or irregular shapes (e.g., not taller-than-wide) and final benign results were significant factors in univariate analysis (p = 0.0002 and p = 0.0013, respectively). However, nodules aspirated by operators with less than 1 year of experience (odds ratio [OR], 3.005; p = 0.0070), and those that had spiculated margins (OR, 6.139; p = 0.0142), isoechogenicity (OR, 10.374; p = 0.0442), or nondiagnostic cytologic findings (OR, 73.637; p = 0.0055) remained significant risk factors after adjustment in multivariable analysis.
CONCLUSION: Thyroid nodule specimens inadequate for BRAF(V600E) mutation analysis were frequently associated with FNA aspiration performed by inexperienced operators, nondiagnostic cytologic findings, benign nodules on final diagnosis, and probably benign ultrasound findings, such as isoechogenicity and not-taller-than-wide shape.

Related: Thyroid Cancer


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