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1.
Crit Rev Oncol Hematol ; 140: 8-16, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31158800

RESUMO

Biliary tract carcinoma (BTC) comprises gallbladder and intra-/extrahepatic cholangiocarcinoma (GBC, ICC, EHC), which are currently classified by anatomical origin. Better understanding of the mutational profile of BTCs might refine classification and improve treatment. We performed a systematic review of studies reporting on mutational profiling of BTC. We included articles reporting on whole-exome/whole-genome-sequencing (WES/WGS) and targeted sequencing (TS) of BTC, published between 2000-2017. Pooled mutation proportions were calculated, stratified by anatomical region and sequencing technique. A total of 25 studies with 1806 patients were included. Overall, TP53 was the most commonly mutated gene in BTC. GBC was associated with mutations in PFKFB3, PLXN2 and PGAP1. Mutations in IDH1, IDH2 and FGFR fusions almost exclusively occurred in ICC patients. Mutations in APC, GNAS and TGFBR2 occurred exclusively in EHC patients. In conclusion, subtypes of BTCs exhibit minor differences in mutational profile, which is likely influenced by the cell of origin.


Assuntos
Neoplasias do Sistema Biliar/genética , Mutação , Proteínas de Neoplasias/genética , Proteína da Polipose Adenomatosa do Colo/genética , Neoplasias do Sistema Biliar/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Isocitrato Desidrogenase/genética , Proteínas de Membrana/genética , Fosfofrutoquinase-2/genética , Monoéster Fosfórico Hidrolases/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética
2.
Ter Arkh ; 91(2): 97-100, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-31094179

RESUMO

MutYH-associated polyposis is the only polyposis syndrome with an autosomal recessive type of inheritance, often phenotypically similar to a weakened form of familial adenomatous polyposis. For the development of the disease mutations in both alleles of the gene are required, but an increased risk of developing colorectal cancer in carriers of monoallelic mutations is noted. The diagnosis of MutYH-associated polyposis should be suspected in a patient with colorectal cancer over 45 years old on the background of polyps in the colon. The review presents modern algorithms for diagnostic and treatment of the disease.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , DNA Glicosilases/genética , Predisposição Genética para Doença/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo
3.
Nat Commun ; 10(1): 2197, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097693

RESUMO

In colorectal cancer (CRC), aberrant Wnt signalling is essential for tumorigenesis and maintenance of cancer stem cells. However, how other oncogenic pathways converge on Wnt signalling to modulate stem cell homeostasis in CRC currently remains poorly understood. Using large-scale compound screens in CRC, we identify MEK1/2 inhibitors as potent activators of Wnt/ß-catenin signalling. Targeting MEK increases Wnt activity in different CRC cell lines and murine intestine in vivo. Truncating mutations of APC generated by CRISPR/Cas9 strongly synergize with MEK inhibitors in enhancing Wnt responses in isogenic CRC models. Mechanistically, we demonstrate that MEK inhibition induces a rapid downregulation of AXIN1. Using patient-derived CRC organoids, we show that MEK inhibition leads to increased Wnt activity, elevated LGR5 levels and enrichment of gene signatures associated with stemness and cancer relapse. Our study demonstrates that clinically used MEK inhibitors inadvertently induce stem cell plasticity, revealing an unknown side effect of RAS pathway inhibition.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Antineoplásicos/uso terapêutico , Biópsia , Sistemas CRISPR-Cas/genética , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Plasticidade Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Intestinos/citologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteômica , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras/metabolismo
4.
J Biochem Mol Toxicol ; 33(7): e22331, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30934153

RESUMO

Exposure to toxic environmental chemicals during pregnancy is a ubiquitous threat to health with potentially transgenerational consequences. However, the underlying mechanism of how transgenerational effects occur as part of environmental chemical exposure are not well understood. We investigated the potential molecular changes associated with dibutyl phthalate exposure that induced transgenerational effects, using a rat model. Through the analysis of the Gene Expression Omnibus database, we found some similar studies of environmental exposure induced transgenerational effects. Then, we analyzed one of the studies and our results to identify the adenomatous polyposis coli (APC) gene. This gene participated the most of the pathways and was upregulated in both studies. We used the miRWALK data set to predict the microRNAs which targeted the APC gene. We confirmed the miR-30 family were significantly downregulated in F3 testis tissues and targeted the APC gene. In conclusion, the miR-30 family/APC interaction is a potential mechanism for the transgenerational effects induced by the environmental chemical.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Exposição Ambiental/efeitos adversos , Infertilidade Masculina/metabolismo , Exposição Materna/efeitos adversos , MicroRNAs/metabolismo , Complicações na Gravidez/metabolismo , Testículo/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Feminino , Infertilidade Masculina/etiologia , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Masculino , Camundongos , MicroRNAs/genética , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Complicações na Gravidez/patologia , Ratos , Ratos Sprague-Dawley , Testículo/patologia
5.
Cell Mol Life Sci ; 76(12): 2463-2476, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028424

RESUMO

Extracellular vesicles (EVs) are membrane-surrounded structures that transmit biologically important molecules from the releasing to target cells, thus providing a novel intercellular communication mechanism. Since EVs carry their cargo in a protected form and their secretion is generally increased in tumorigenesis, EVs hold a great potential for early cancer diagnosis. By 3D culturing, we provide evidence that colorectal cancer (CRC) patient-derived organoids, representing a state-of-the-art established and essential approach for studying human CRC, is a suitable model for EV analysis. When testing the effects of major factors promoting CRC progression on EV release in the organoid model, we observed that Apc mutation, leading to uncontrolled Wnt activation and thus to tumorigenesis in the vast majority in CRC patients, critically induces EV release by activating the Wnt pathway. Furthermore, the extracellular matrix component collagen, known to accumulate in tumorigenesis, enhances EV secretion as well. Importantly, we show that fibroblast-derived EVs induce colony formation of CRC organoid cells under hypoxia. In contrast, there was no major effect of tumor cell-derived EVs on the activation of fibroblasts. Collectively, our results with CRC and Apc-mutant adenoma organoids identify Apc mutation and collagen deposition as critical factors for increasing EV release from tumors. Furthermore, we provide evidence that stromal fibroblast-derived EVs contribute to tumorigenesis under unfavorable conditions in CRC.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/patologia , Vesículas Extracelulares/patologia , Intestinos/patologia , Organoides/patologia , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Progressão da Doença , Vesículas Extracelulares/genética , Humanos , Camundongos Endogâmicos C57BL , Mutação , Organoides/metabolismo , Células Tumorais Cultivadas , Via de Sinalização Wnt
6.
Int J Biol Markers ; 34(1): 80-89, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30852976

RESUMO

BACKGROUND: The goal of this study was to screen point mutations and deletions in APC and MUTYH genes in patients suspected of familial adenomatous polyposis (FAP) in a Brazilian cohort. METHODS: We used high-resolution melting, Sanger direct sequencing and multiplex ligation-dependent probe association (MLPA) assays to identify point mutations, and large genomic variations within the coding regions of APC and MUTYH genes. RESULTS: We identified 19 causative mutations in 40 Brazilian patients from 20 different families. Four novel mutations were identified in the APC gene and two in the MUTYH gene. We also found a high intra- and inter-familial diversity regarding extracolonic manifestations, and gastric polyps were the most common manifestation found in our cohort. CONCLUSION: We believe that the FAP mutational spectrum can be population-specific and screening FAP patients in different populations can improve pre-clinical diagnosis and improve clinical conduct.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , DNA Glicosilases/genética , Predisposição Genética para Doença , Mutação , Polipose Adenomatosa do Colo/patologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Adulto Jovem
7.
Science ; 363(6433): 1345-1349, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30898933

RESUMO

Excessive consumption of beverages sweetened with high-fructose corn syrup (HFCS) is associated with obesity and with an increased risk of colorectal cancer. Whether HFCS contributes directly to tumorigenesis is unclear. We investigated the effects of daily oral administration of HFCS in adenomatous polyposis coli (APC) mutant mice, which are predisposed to develop intestinal tumors. The HFCS-treated mice showed a substantial increase in tumor size and tumor grade in the absence of obesity and metabolic syndrome. HFCS increased the concentrations of fructose and glucose in the intestinal lumen and serum, respectively, and the tumors transported both sugars. Within the tumors, fructose was converted to fructose-1-phosphate, leading to activation of glycolysis and increased synthesis of fatty acids that support tumor growth. These mouse studies support the hypothesis that the combination of dietary glucose and fructose, even at a moderate dose, can enhance tumorigenesis.


Assuntos
Carcinogênese/patologia , Dieta/efeitos adversos , Xarope de Milho Rico em Frutose/efeitos adversos , Neoplasias Intestinais/patologia , Carga Tumoral , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Xarope de Milho Rico em Frutose/administração & dosagem , Camundongos , Camundongos Mutantes , Gradação de Tumores
8.
J Cancer Res Clin Oncol ; 145(5): 1111-1122, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887153

RESUMO

PURPOSE: ApcMin/+ mouse is an excellent animal model bearing multiple intestinal neoplasia, used to simulate human familial adenomatous polyposis and colorectal tumors. The key point of this model is the mutation of Apc gene, which is a significant tumor-suppressor gene in the Wnt signaling pathway. There are also some other possible mechanisms responsible for the development of colorectal tumors in the ApcMin/+ mouse model, such as tumor-associated signaling pathways activation, the changes of tumor-related genes, and the involvement of some related proteins or molecules. METHODS: The relevant literatures about ApcMin/+ mouse model from PUBMED databases are reviewed in this study. RESULTS: In recent years, increasing studies have focused on the application of ApcMin/+ mouse model in colorectal tumor, trying to find effective therapeutic targets for further use. CONCLUSION: This article will give a brief review on the related molecular mechanisms of the ApcMin/+ mouse model and its application in colorectal tumor researches.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Pesquisa , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Biomarcadores Tumorais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/metabolismo , Reparo do DNA , Epigênese Genética , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Fenótipo , Transdução de Sinais
9.
Medicine (Baltimore) ; 98(12): e14781, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30896620

RESUMO

RATIONALE: The prevalence of anastomotic recurrence (AR) in colorectal cancer (CRC) after resection of the primary tumor (PT) is 5% to 14%. However, no association has been observed between specific somatic genetic alterations and AR. Such associations may shed light on the mechanism of AR. PATIENT CONCERNS: We experienced 2 patients with AR of CRC. The first patient was a 42-year-old woman who underwent resection of an AR of rectal cancer 2 times within 19 months after resection of the PT. The second patient was a 77-year-old woman who underwent resection of an AR of ascending colon cancer twice within 38 months after resection of the PT. DIAGNOSIS: Both cases were diagnosed as repetitive AR. INTERVENTIONS: Loss of heterozygosity analysis, microsatellite instability (MSI) study of 9 microsatellite loci, and mutational analysis of KRAS, BRAF, APC, TP53, and SMAD4 were performed. OUTCOMES: All the lesions, except 1, harbored mutations in APC, KRAS, and TP53, without MSI, after neoadjuvant chemoradiotherapy. The APC, KRAS, and TP53 mutations were pathogenic or likely pathogenic in the PTs and ARs. Both women harbored the same KRAS G13D mutation, which accounts for 8% of all KRAS mutations in sporadic CRC s. The probability of the incidental occurrence of KRAS G13D mutations in both cases is 0.64%, provided that the mutations were independent of AR. LESSONS: Our findings may shed light on the mechanism of AR in CRC, namely, that the PT harbored the same mutations as the AR and the lesions in both cases harbored the KRAS G13D mutation.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Recidiva Local de Neoplasia/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Feminino , Humanos , Instabilidade de Microssatélites , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Proteína Supressora de Tumor p53/genética
10.
Mol Carcinog ; 58(6): 1008-1018, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30720232

RESUMO

Sohlh2 belongs to the superfamily of basic helix-loop-helix (bhlh) transcription factors. Aberrant expression of bhlh transcription factors has been shown to be associated with multiple tumorigenesis. We previously identified that sohlh2 functioned as a tumor suppressor in ovarian cancer. Here, we examined the expression levels of sohlh2 in human breast cancer and its potential role in disease pathogenesis. The results of sohlh2 immunohistochemistry (IHC) and Western blot analysis demonstrated the decreased sohlh2 expression in breast cancer specimens as compared to adjacent noncancerous tissues. Through in vitro MTT, BrdU, colony formation and cell cycle assays and in vivo tumor xenograft studies, we showed that forced expression of sohlh2 led to a significant reduction in proliferation due to G1 arrest in vitro and tumorigenesis in nude mice. Conversely, silencing of sohlh2 enhanced breast cancer cell proliferation. Furthermore, we confirmed that sohlh2 inhibited breast cancer cell proliferation by suppressing the Wnt/ß-catenin signaling pathway. APC was the direct target of sohlh2, and mediated the inhibitory activities of sohlh2 on Wnt/ß-catenin signaling pathway. Thus, our data indicate that sohlh2 likely functions as a tumor suppressor in breast cancer that is mediated by repressing Wnt/ß-catenin signaling pathway via upregulation of APC expression.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Neoplasias da Mama/patologia , Regulação para Baixo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Células MCF-7 , Camundongos , Transplante de Neoplasias , Regiões Promotoras Genéticas , Via de Sinalização Wnt
11.
Nat Commun ; 10(1): 724, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760710

RESUMO

Bcl9 and Pygo are Wnt enhanceosome components that effect ß-catenin-dependent transcription. Whether they mediate ß-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (ApcMin), or by Apc1322T encoding a partially-functional Apc truncation commonly found in colorectal carcinomas. Intestinal deletion of Bcl9 extends disease-free survival in both models, and essentially cures Apc1322T mice of their neoplasia. Loss-of-Bcl9 synergises with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages. Bcl9 loss also promotes tumour retention in ApcMin mice, apparently via relocating nuclear ß-catenin to the cell surface, but this undesirable effect is not seen in Apc1322T mice whose Apc truncation retains partial function in regulating ß-catenin. Our results demonstrate a key role of the Wnt enhanceosome in ß-catenin-dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Carcinogênese , Mucosa Intestinal/metabolismo , Neoplasias Intestinais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Adenoma , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Transformação Celular Neoplásica , Neoplasias Colorretais , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Genes APC , Intestinos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição , Via de Sinalização Wnt , beta Catenina/metabolismo
12.
Nutrients ; 11(1)2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30650553

RESUMO

The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States, n-6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of n-6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (n-6HFD) on CpG methylation of Fxr and prostaglandin-endoperoxide synthase-2 (Ptsg-2) genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli (Apc) and proliferative cyclin D1 (Ccnd1) genes. Weaned C57BL/6J male mice were fed for 6 weeks either an n-6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the n-6HFD had reduced (60%) Fxr promoter CpG methylation and increased (~50%) Fxr mRNA. The expression of FXR-target ileal bile acid-binding protein (Ibabp), small heterodimer protein (Shp), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The n-6HFD reduced Ptgs-2 CpG methylation, increased the expression of Cox-2, and increased Apc CpG methylation in colonic mucosa. Accordingly, reduced expression of Apc was coupled to accumulation of c-JUN and Ccnd1, respectively cofactor and gene targets for the ß-catenin/Wnt signaling pathway. Finally, the n-6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an n-6HFD epigenetically modifies Fxr, leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of Ptsg-2 coupled with silencing of Apc and accumulation of C-JUN and Ccnd1 may increase the risk of inflammation and cancer of the colon.


Assuntos
Colo/efeitos dos fármacos , Neoplasias do Colo/etiologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Inflamação/etiologia , Mucosa Intestinal/efeitos dos fármacos , Ácido Linoleico/efeitos adversos , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Células Cultivadas , Colite/etiologia , Colite/genética , Colite/metabolismo , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Pesquisa Fetal , Genes jun , Humanos , Inflamação/genética , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ácido Linoleico/farmacologia , Camundongos Endogâmicos C57BL , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
13.
Int J Cancer ; 145(2): 390-400, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30613976

RESUMO

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.


Assuntos
Neoplasias da Mama Masculina/genética , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação , Análise de Sequência de DNA/métodos , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , DNA Glicosilases/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Mol Cancer Ther ; 18(2): 346-355, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30425131

RESUMO

PIK3CA mutations are common in clinical molecular profiling, yet an effective means to target these cancers has yet to be developed. MTORC1 inhibitors are often used off-label for patients with PIK3CA mutant cancers with only limited data to support this approach. Here we describe a cohort of patients treated with cancers possessing mutations activating the PI3K signaling cascade with minimal benefit to treatment with the MTORC1 inhibitor everolimus. Previously, we demonstrated that dual PI3K/mTOR inhibition could decrease proliferation, induce differentiation, and result in a treatment response in APC and PIK3CA mutant colorectal cancer. However, reactivation of AKT was identified, indicating that the majority of the benefit may be secondary to MTORC1/2 inhibition. TAK-228, an MTORC1/2 inhibitor, was compared with dual PI3K/mTOR inhibition using BEZ235 in murine colorectal cancer spheroids. A reduction in spheroid size was observed with TAK-228 and BEZ235 (-13% and -14%, respectively) compared with an increase of >200% in control (P < 0.001). These spheroids were resistant to MTORC1 inhibition. In transgenic mice possessing Pik3ca and Apc mutations, BEZ235 and TAK-228 resulted in a median reduction in colon tumor size of 19% and 20%, respectively, with control tumors having a median increase of 18% (P = 0.02 and 0.004, respectively). This response correlated with a decrease in the phosphorylation of 4EBP1 and RPS6. MTORC1/2 inhibition is sufficient to overcome resistance to everolimus and induce a treatment response in PIK3CA mutant colorectal cancers and deserves investigation in clinical trials and in future combination regimens.


Assuntos
Benzoxazóis/administração & dosagem , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mutação , Pirimidinas/administração & dosagem , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Estudos de Coortes , Neoplasias Colorretais/genética , Feminino , Humanos , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Camundongos , Camundongos Transgênicos , Pirimidinas/farmacologia , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Biochimie ; 157: 64-71, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30414835

RESUMO

Colorectal cancer (CRC) is one of the most common forms of solid tumors in the world with high rates of mortality and morbidity. Most cases of CRCs are initiated by inactivating mutations in a tumor suppressor gene, adenomatous polyposis coli (APC), leading to constitutive activation of the Wnt signaling pathway. This review summarizes the roles of somatic and germline mutations of the APC gene in hereditary as well as sporadic forms of CRC. We also discuss the diagnostic and prognostic value of the APC gene in the pathogenesis of CRC for a better understanding of CRC disease.


Assuntos
Proteína da Polipose Adenomatosa do Colo , Neoplasias Colorretais , Mutação em Linhagem Germinativa , Via de Sinalização Wnt , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos
16.
Mucosal Immunol ; 12(1): 164-177, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30279518

RESUMO

Polysaccharide A (PSA), an immunogenic capsular component of non-toxigenic Bacteroides fragilis (NTBF) strain NCTC 9343, is reported to promote mucosal immune development and suppress colitis. Contrastingly, enterotoxigenic Bacteroides fragilis (ETBF) is highly associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC), rapidly inducing IL-17-dependent murine colitis and tumorigenesis. In specific-pathogen-free (SPF) C57BL/6 wild-type (WT) and multiple intestinal neoplasia (MinApc716+/-) mice, we show that sequential treatment of the NTBF strain, 9343, followed by the ETBF strain, 86-5443-2-2 (86), diminished colitis and tumorigenesis. Mice treated simultaneously with 9343 and 86 exhibited both severe colitis and tumorigenesis. Abrogated disease severity in sequentially treated mice was attributed to 9343 strain dominance and decreased IL-17A, but 86 colonization prior to or simultaneous with 9343 mitigated the anti-inflammatory effect of 9343. Remarkably, 9343-mediated protection was independent of PSA, as sequentially treated mice receiving ΔPSA 9343 exhibited similar protection. Further, SPF WT and Min mice colonized with PSA-competent or PSA-deficient 9343 exhibited similar IL-10, IL-17, and IFN-γ responses. Treatment of 86-colonized mice with 9343 failed to disrupt 86 pathogenesis. Our findings demonstrate that 9343 colonization, independent of PSA, offers prophylaxis against colitis-inducing 86 but may not be a valid therapy once colitis is established.


Assuntos
Bacteroides fragilis/imunologia , Colite/imunologia , Neoplasias Colorretais/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Células Th17/imunologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Bacteroides fragilis/patogenicidade , Carcinogênese , Células Cultivadas , Colite/induzido quimicamente , Modelos Animais de Doenças , Humanos , Interleucina-17/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ácido Trinitrobenzenossulfônico
17.
Cancer ; 125(5): 690-697, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30480775

RESUMO

BACKGROUND: Genetic assessment in Ashkenazi Jewish (AJ) patients often is limited to BRCA1/2 founder mutation testing. With access to time-efficient and cost-efficient multigene panel testing, some advocate expanding genetic testing in this population. However, to the best of the authors' knowledge, rates of nonfounder BRCA1/2 mutations and mutations in cancer-associated genes other than BRCA1/2 among AJ are not known. In the current study, the authors sought to assess the prevalence of mutations other than BRCA1/2 founder mutations among AJ patients undergoing genetic assessment. METHODS: The authors reviewed the medical records for all AJ patients who underwent genetic assessment at a single institution between June 2013 and December 2016. Mutations were categorized as 1) BRCA1/2 AJ founder mutations (BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT); 2) nonfounder BRCA1/2 mutations; or 3) mutations in non-BRCA1/2 cancer-associated genes. RESULTS: A total of 732 AJ patients underwent genetic assessment. Of these, 371 patients (51%) had a personal history of breast or ovarian cancer, 540 patients (73.8%) had a family history of breast cancer, and 132 patients (18%) had a family history of ovarian cancer. In the study population, 101 patients (13.8%) were found to have a pathogenic mutation, 78 patients (10.7%) had a BRCA1/2 founder mutation, 3 patients (0.4%) had a nonfounder BRCA1/2 mutation, and 20 patients (2.7%) had a mutation in a non-BRCA1/2 cancer-associated gene. Non-BRCA1/2 cancer-associated genes harboring mutations included RAD51D, TP53, mutS homolog 6 (MSH6), checkpoint kinase 2 (CHEK2), adenomatous polyposis coli (APC), and Fanconi anemia group C protein (FANCC). CONCLUSIONS: Among AJ patients found to have a pathogenic mutation on genetic assessment, approximately 22.8% had a mutation that would be missed with BRCA1/2 AJ founder mutation testing. Comprehensive multigene panel sequencing can provide clinically relevant genetic information for AJ patients and should be considered for genetic assessment in this population.


Assuntos
Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Judeus/genética , Análise de Sequência de DNA/métodos , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Quinase do Ponto de Checagem 2/genética , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Prevalência , Proteína Supressora de Tumor p53/genética , Adulto Jovem
18.
Brain Tumor Pathol ; 36(1): 1-6, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30523493

RESUMO

Expression of the ALK gene strongly correlates with the WNT-activated medulloblastomas, which are routinely identified by detection of CTNNB1 mutation. However, some tumors have mutations in other than CTNNB1 genes. Therefore, we investigated if ALK expression may identify WNT-activated tumors without CTNNB1 mutation. In addition, we examined if ALK expression may differentiate WNT-activated medulloblastoma from other malignant posterior fossa tumors. ALK expression was analyzed using immunohistochemistry (clone D5F3) in 70 patients with posterior fossa tumours. Among 55 medulloblastomas, 6 tumors showed ALK expression in > 50% of tumor cells. In one tumor, with ALK positive reaction, negative nuclear reaction against ß-catenin and the lack of CTNNB1 mutation, next generation sequencing revealed a presence of pathogenic variant c.3366_3369del in the APC gene, with homozygous deletion leading to inactivation of both copies in tumor cells. MLPA analysis displayed the presence of chromosome 6 monosomy, therefore, confirming the WNT type of this tumor. All analyzed 19 anaplastic ependymomas, 4 choroid plexus carcinomas and 2 atypical teratoid rhabdoid tumors were immunonegative for ALK expression. Therefore, we propose, that immunohistochemical detection of ALK protein should be highly recommended in routine investigation, in parallel to already established methods for identification and differentiation of WNT-activated medulloblastoma.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Infratentoriais/diagnóstico , Neoplasias Infratentoriais/genética , Meduloblastoma/diagnóstico , Meduloblastoma/genética , Mutação , beta Catenina/genética , Adolescente , Criança , Pré-Escolar , Diagnóstico por Computador , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Lactente , Neoplasias Infratentoriais/classificação , Masculino , Meduloblastoma/classificação , Via de Sinalização Wnt
19.
Mol Genet Genomic Med ; 7(1): e00505, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30523670

RESUMO

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease which primarily manifested with developing adenomas or polyps in colon or rectum. It is caused by the germline mutations in adenomatous polyposis coli (APC) gene. Patients with FAP are usually manifested with "hundreds or even thousands" adenomas or polyps in colon or rectum. However, without proper clinical diagnosis and timely surgical interventions, colorectal adenomas, or polyps gradually increase in size and in numbers which finally leads to colorectal cancer (CRC) at the mean age of 36 years of the patient. METHODS: In this study, we identified a family with FAP. In this family, FAP has been diagnosed clinically based on symptoms, medical test reports, and positive family history for three generations. In order to unveil the molecular genetic consequences underlying the disease phenotype, we performed next-generation sequencing with a customized and designed panel of genes reported to be associated with hereditary CRC. The variant identified by next-generation sequencing has been validated by Sanger sequencing. RESULTS: A heterozygous novel insertion [c.3992_3993insA; p.Thr1332Asnfs*10] in exon 16 of APC gene has been identified. This novel insertion is cosegregated well with the FAP phenotype among all the affected members of this family. This mutation causes a frameshift by the formation of a premature stop codon which finally results in the formation of a truncated APC protein of 1,342 amino acids instead of the wild type APC protein of 2,843 amino acids. Hence, this is a loss-of-function mutation. This mutation was not found in unaffected family members or in normal control individuals. CONCLUSION: Our present study emphasizes the importance of a novel approach of the gene panel-based high-throughput sequencing technology for easy and rapid screening for patients with FAP or CRC which will help the clinician for follow-up and management.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Mutação em Linhagem Germinativa , Polimorfismo de Nucleotídeo Único , Polipose Adenomatosa do Colo/patologia , Adulto , Feminino , Testes Genéticos/métodos , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA/métodos
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