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1.
Gastroenterology ; 157(5): 1222-1232.e4, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31419435

RESUMO

BACKGROUND AND AIMS: In patients who have undergone surgery for colorectal cancer (CRC), 3% have recurrence of (metachronous) CRC. We investigated whether tumor seeding during colonoscopy (iatrogenic implantation of tumor cells in damaged mucosa) increases risk for metachronous CRC. METHODS: In a proof of principle study, we collected data from the Dutch National Pathology Registry for patients with a diagnosis of CRC from 2013 through 2015, with a second diagnosis of CRC within 6 months to 3.5 years after surgery. We reviewed pathology reports to identify likely metachronous CRC (histologically proven adenocarcinoma located elsewhere in the colon or rectum from the surgical anastomosis). For 22 patients fulfilling the inclusion criteria, we ascribed the most likely etiology to tumor seeding when endoscopic manipulations, such as biopsies or polypectomy, occurred at the location where the metachronous tumor was subsequently detected, after endoscopic manipulation of the primary tumor. We collected clinical data from patients and compared molecular profiles of the primary and metachronous colorectal tumors using next-generation sequencing. We then examined the source of seeded tumor. We tested whether tumor cells stay behind in the working channel of the endoscope after biopsies of colorectal tumors, and whether these cells maintain viability in organoid cultures. RESULTS: In total, tumor seeding was suspected as the most likely etiology of metachronous CRC in 5 patients. Tumor tissues were available from 3 patients. An identical molecular signature was observed in the primary and metachronous colorectal tumors from all 3 patients. In 5 control cases with a different etiology of metachronous CRC, the molecular signature of the primary and metachronous tumor were completely different. Based on review of 2147 patient records, we estimated the risk of tumor seeding during colonoscopy to be 0.3%-0.6%. We demonstrated that the working channel of the colonoscope becomes contaminated with viable tumor cells during biopsy collection. Subsequent instruments introduced through this working channel also became contaminated. These cells were shown to maintain their proliferative potential. CONCLUSIONS: In an analysis of primary and secondary tumors from patients with metachronous CRC, we found that primary tumor cells might be seeded in a new location after biopsy of the primary tumor. Although our study does not eliminate other possibilities of transmission, our findings and experiments support the hypothesis that tumor seeding can occur during colonoscopy via the working channel of the endoscope. The possibility of iatrogenic seeding seems low. However, our findings compel awareness on this potentially preventable cause of metachronous CRC.


Assuntos
Pólipos Adenomatosos/cirurgia , Pólipos do Colo/cirurgia , Colonoscopia/efeitos adversos , Neoplasias Colorretais/cirurgia , Inoculação de Neoplasia , Segunda Neoplasia Primária/patologia , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patologia , Idoso , Biomarcadores Tumorais/genética , Pólipos do Colo/genética , Pólipos do Colo/patologia , Colonoscópios , Colonoscopia/instrumentação , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Contaminação de Equipamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/genética , Estudo de Prova de Conceito , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral , Células Tumorais Cultivadas
2.
Gastroenterology ; 157(4): 949-966.e4, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323292

RESUMO

In addition to the adenoma to carcinoma sequence, colorectal carcinogenesis can occur via the serrated pathway. Studies have focused on clarification of categories and molecular features of serrated polyps, as well as endoscopic detection and risk assessment. Guidelines from the World Health Organization propose assigning serrated polyps to categories of hyperplastic polyps, traditional serrated adenomas, and sessile serrated lesions (SSLs). Traditional serrated adenomas and SSLs are precursors to colorectal cancer. The serrated pathway is characterized by mutations in RAS and RAF, disruptions to the Wnt signaling pathway, and widespread methylation of CpG islands. Epidemiology studies of serrated polyps have been hampered by inconsistencies in terminology and reporting, but the prevalence of serrated class polyps is 20%-40% in average-risk individuals; most serrated polyps detected are hyperplastic. SSLs, the most common premalignant serrated subtype, and are found in up to 15% of average-risk patients by high-detecting endoscopists. Variations in rate of endoscopic detection of serrated polyps indicate the need for careful examination, with adequate bowel preparation and sufficient withdrawal times. Risk factors for SSLs include white race, family history of colorectal cancer, smoking, and alcohol intake. Patients with serrated polyps, particularly SSLs and traditional serrated adenomas, have an increased risk of synchronous and metachronous advanced neoplasia. Surveillance guidelines vary among countries, but SSLs and proximal hyperplastic polyps require special attention in assignment of surveillance interval-especially in light of concerns regarding incomplete detection and resection.


Assuntos
Pólipos Adenomatosos , Carcinoma , Pólipos do Colo , Neoplasias Colorretais , Terminologia como Assunto , Pólipos Adenomatosos/classificação , Pólipos Adenomatosos/epidemiologia , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/terapia , Biomarcadores Tumorais/genética , Carcinoma/classificação , Carcinoma/epidemiologia , Carcinoma/genética , Carcinoma/terapia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Pólipos do Colo/classificação , Pólipos do Colo/epidemiologia , Pólipos do Colo/genética , Pólipos do Colo/terapia , Neoplasias Colorretais/classificação , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Predisposição Genética para Doença , Variação Genética , Humanos , Fenótipo , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco
4.
EBioMedicine ; 44: 334-345, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31122841

RESUMO

BACKGROUND: Energy metabolism in carcinogenesis is poorly understood. It is widely accepted the majority of colorectal cancers (CRCs) arise from adenomatous polyps (APs). We aimed to characterize the bioenergetic alterations in APs and CRCs. METHODS: Fifty-six APs, 93 CRCs and adjacent normal mucosae were tested. Oxygen consumption rate (OCR) was measured representing mitochondrial oxidative phosphorylation (OxPhos), and extracellular acidification rate (ECAR)was measured representing glycolysis. Mitochondrial DNA (mtDNA) variants and mutations were studied. Over-expressed metabolic genes in APs were identified by microarray and validated by qRT-PCR, Western blots and immunohistochemistry. Identified genes were knocked down in WiDr and colo205 CRC cell lines, and their expression was analyzed in APs/CRCs with enhanced glycolysis. FINDINGS: ECAR, not OCR, was significantly increased in APs. While no difference of ECAR was found between CRCs and normal mucosae, OCR was significantly reduced in CRCs. OCR/ECAR ratio was decreased in APs over 1 cm, APs with a villous component and CRCs, indicating their glycolytic tendencies. The number of mtDNA mutations was increased in APs and CRCs, but not correlated with metabolic profiles. Two metabolic genes ALDOB and SLC16A4 were up-regulated in APs. Both ALDOB-knockdown and SLC16A4-knockdown CRC cell lines showed increased basal motichondrial OxPhos and decreased basal glycolysis. Moreover, the increase of mitochondrial ATP-linked respiration and the decrease of glycolytic capacity were showed in SLC16A4-knockdown cells. Finally, APs/CRCs with enhanced glycolysis had increased SLC16A4 expression. INTERPRETATION: ATP production shifts from OxPhos to glycolysis in the process of AP enlargement and villous transformation. OxPhos defects are present in CRCs but not in APs. APs and CRCs tend to accumulate mtDNA mutations, but these are not correlated with bioenergetic profiles. Finally, the ALDOB and SLC16A4 may contribute to the glycolytic shift in APs/CRCs.


Assuntos
Adenocarcinoma/metabolismo , Pólipos Adenomatosos/metabolismo , Neoplasias Colorretais/metabolismo , Metabolismo Energético , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/genética , Adenocarcinoma/patologia , Pólipos Adenomatosos/diagnóstico por imagem , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Linhagem Celular Tumoral , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA Mitocondrial , Feminino , Fluordesoxiglucose F18 , Humanos , Mucosa Intestinal , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Mutação , Estadiamento de Neoplasias , Fosforilação Oxidativa , Consumo de Oxigênio , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Carga Tumoral
5.
Histopathology ; 75(1): 81-87, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30825335

RESUMO

AIMS: Sessile serrated lesions (SSL) with dysplasia are uncommon polyps with a high risk of rapid malignant transformation. Most of these lesions have a BRAF mutation and 75% show loss of MLH1 expression in their dysplastic component. Different morphological patterns of dysplasia occurring in these polyps have recently been described. We hypothesised that a subset of SSLs with dysplasia mimicking the dysplasia seen in conventional adenoma (adenomatous dysplasia) may represent a collision lesion between an ordinary SSL and a conventional adenoma. METHODS AND RESULTS: We selected 80 SSLs with dysplasia, including 19 with adenomatous dysplasia, 18 with serrated dysplasia and 43 with dysplasia not otherwise specified (NOS). BRAF mutation analysis was performed using molecular testing (allelic discrimination) and the mutation-specific BRAF-V600E immunohistochemistry (clone VE1). The overall BRAF-V600E mutation rate was 84% in all lesions, 68% in SSLs with adenomatous dysplasia, 89% in SSLs with serrated dysplasia and 88% in SSLs with dysplasia NOS. From the 63 SSLs with dysplasia that were positive for the BRAF-V600E mutation, a negative BRAF-V600E immunostaining was observed in the dysplastic component of 83% of SSLs with adenomatous dysplasia, 0% of SSLs with serrated dysplasia and 3% of SSLs with dysplasia NOS (P < 0.001). CONCLUSIONS: These findings suggest that SSLs with adenomatous dysplasia may not represent advanced SSLs, but instead may be a collision between a non-dysplastic SSL and a conventional adenoma.


Assuntos
Adenoma/genética , Adenoma/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Pólipos Intestinais/genética , Pólipos Intestinais/patologia , Proteínas Mutantes/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adenoma/metabolismo , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/metabolismo , Pólipos Adenomatosos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pólipos Intestinais/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Estudos Retrospectivos
6.
Z Gastroenterol ; 57(4): 497-500, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30873576

RESUMO

Juvenile polyposis syndrome is a rare autosomal-dominant disorder characterized by multiple hamartomatous polyps in the gastrointestinal tract. It is associated with an increased risk of gastrointestinal cancer. We report the case of a 49-year-old woman presenting with proximal muscle weakness, weight loss, severe anemia, and melena. One year before, the diagnosis of a "fundic gland polyposis" was presumed after endoscopic evaluation for iron deficiency anemia had shown numerous polyps limited to the gastric mucosa. On admission, the diagnosis of dermatomyositis was made based on laboratory results with a marked elevated creatine kinase as well as the presence of characteristic clinical findings and muscle histology. Upper endoscopy revealed multiple pedunculated, edematous polyps in the stomach without apparent cancerous lesions intraluminally. Infiltration of the muscular layer was not detectable on endoscopic ultrasound. Histopathological examination of the polyps showed smooth outer surfaces and multiple dilated cystic glands, consistent with hamartomatous juvenile-type polyps. Magnetic resonance imaging revealed a peritoneal mass close to the greater curvature of the stomach, which was identified as a poorly differentiated adenocarcinoma by laparoscopic sampling. Immunohistochemical analysis of resected polyps was remarkable for a loss of SMAD4 expression, a finding that is very commonly observed in patients with gastric juvenile polyposis syndrome. Despite initial treatment response to glucocorticoids and chemotherapy, the patient died 5 months later due to progressive illness. Patients with gastric juvenile polyposis and SMAD4 mutations are at a high risk of developing gastric cancer; hence, early gastrectomy should be considered.


Assuntos
Dermatomiosite/complicações , Polipose Intestinal/congênito , Polipose Intestinal/diagnóstico por imagem , Síndromes Neoplásicas Hereditárias/diagnóstico por imagem , Pólipos/complicações , Pólipos/genética , Proteína Smad4/genética , Neoplasias Gástricas/complicações , Neoplasias Gástricas/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/genética , Adolescente , Dermatomiosite/patologia , Endoscopia do Sistema Digestório , Evolução Fatal , Feminino , Humanos , Polipose Intestinal/patologia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Gástricas/patologia
7.
Med Mol Morphol ; 52(2): 82-89, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30128768

RESUMO

Colorectal cancer (CRC) placed among the most common neoplasm. Survivin is a member of the inhibitor apoptosis gene family. This gene could be associated with aggressive behavior in numerous types of cancers. The aim of the present study was to evaluate the immunohistochemical expression of survivin gene and its correlation with -31G/C polymorphism in CRC patients. This case-control study was performed on 90 cases: 30 adenocarcinoma, 30 adenomatous polyp, and 30 normal colon. Immunohistochemical expression of survivin evaluated on formalin-fixed paraffin-embedded tissue and -31G/C polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. Results showed that the subjects carrying C/C genotype with 43.3% (p = 0.002' OR = 12.188, CI = 2.530-58.720) and G/C genotype with 43.3% (p = 0.032' OR = 4.432, CI = 1.133-17.341) significantly had increased risk of CRC compared with subjects carrying GG genotype. Allelic frequencies showed statistically significant difference (p = 0.001) among adenocarcinoma (G = 35%, C = 65%), adenomatous (G = 43.3, C = 56.7), and normal group (G = 68.3, C = 31.7). Immunohistological evaluation showed nuclear survivin protein expression in patients with the CC genotype higher than in patient with the GG and GC genotypes (p = 0.002). The results suggest that C allele of - 31G/C polymorphism in survivin might be cooperative in CRC development.


Assuntos
Adenocarcinoma/genética , Pólipos Adenomatosos/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Survivina/genética , Adenocarcinoma/metabolismo , Pólipos Adenomatosos/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/metabolismo , Feminino , Frequência do Gene , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Survivina/biossíntese
8.
Fam Cancer ; 18(2): 165-172, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30196345

RESUMO

Relatively little is known on the genotype-phenotype correlations between SMAD4 gene mutations, juvenile polyposis of the intestine and Hereditary Hemorrhagic Teleangectasia. We describe a family in which the proband (a 46-year old woman) had massive polyposis of the stomach-leading to surgery-with high-grade dysplasia at histology. Molecular analysis was carried out using Next Generation sequencing techniques with Miseq Illumina Platforms and a minimal coverage of 40 reads. In the proband, the analysis showed the presence of a truncating mutation in the SMAD4 gene (c.1213dupC, a variant previously associated with juvenile polyposis and Hereditary Hemorrhagic Teleangectasia). The same mutation was detected in two other members of the family (father and brother of the proband), who showed massive polypoid involvement of the stomach at gastroscopy. By taking the family history, subtle evidence of Hereditary Teleangectasia was found (nasal bleeding and arterovenous malformations) in the three gene carriers. Colonoscopy showed polyp occurrence in all three affected members with SMAD4 mutation, with prevalence of adenomatous lesions in one (father), of hamartomas in the brother, and of a mix of histological types in the proband. The main features of the family can be summarized as follows: (A) In hereditary juvenile polyposis, lesions of different histology can be detected at colonoscopy; (B) In the gene carriers of SMAD4 mutations, lesions of the stomach require careful surveillance and, when necessary, surgical interventions; (C) Signs and symptoms of Hereditary Hemorrhagic Teleangectasia should be suspected (and searched) in individuals with SMAD4 constitutional mutations.


Assuntos
Adenocarcinoma/genética , Pólipos Adenomatosos/genética , Polipose Intestinal/congênito , Síndromes Neoplásicas Hereditárias/genética , Proteína Smad4/genética , Neoplasias Gástricas/genética , Telangiectasia Hemorrágica Hereditária/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/cirurgia , Feminino , Gastrectomia , Gastroscopia , Heterozigoto , Humanos , Polipose Intestinal/diagnóstico , Polipose Intestinal/genética , Polipose Intestinal/patologia , Polipose Intestinal/cirurgia , Masculino , Anamnese , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/patologia , Síndromes Neoplásicas Hereditárias/cirurgia , Fenótipo , Estômago/diagnóstico por imagem , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Telangiectasia Hemorrágica Hereditária/diagnóstico
9.
Digestion ; 99(1): 33-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30554192

RESUMO

BACKGROUND: Colorectal cancers (CRCs) develop through the accumulation of genetic and epigenetic alterations of oncogenes and tumor suppressor genes. In addition to the well-characterized adenoma-carcinoma sequence, the serrated neoplasia pathway is now recognized as an alternative pathway for CRC development. SUMMARY: Through analysis of the colonoscopic, pathological, and molecular features of colorectal tumors, we identified a novel microsurface structure characteristic of serrated lesions. The Type II-Open (Type II-O) pit pattern is highly specific to sessile serrated adenoma/polyps (SSA/Ps), and Type-II-O-positive tumors frequently exhibit v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and 5'-C-phosphate-G-3' (CpG) island hypermethylation. By screening DNA methylation associated with the development of serrated lesions, we detected methylation of secreted protein acidic and rich in cysteine (SPARC)-related modular calcium binding 1 (SMOC1) in traditional serrated adenomas (TSAs). Epigenetic silencing of SMOC1 is prevalent among TSAs but it is rarely observed in SSA/Ps, which suggests SMOC1 could be a useful diagnostic marker of serrated lesions. We also searched for epigenetic alterations associated with the growth pattern of colorectal tumors and found that methylation of neurotensin receptor 1 is associated with lateral and non-invasive tumor growth. Key Message: Through the summarized studies, we have been able to identify novel morphological and molecular features that could contribute to a better understanding of colorectal tumors and to improved clinical diagnosis.


Assuntos
Adenoma/genética , Carcinogênese/genética , Neoplasias Colorretais/genética , Adenoma/patologia , Pólipos Adenomatosos/complicações , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patologia , Carcinogênese/patologia , Pólipos do Colo/complicações , Pólipos do Colo/genética , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Ilhas de CpG/fisiologia , Metilação de DNA/genética , Epigênese Genética , Humanos , Osteonectina/fisiologia , Proteínas Proto-Oncogênicas B-raf/fisiologia
10.
J Gastroenterol Hepatol ; 34(2): 383-389, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30554426

RESUMO

BACKGROUND AND AIM: The relationship between a family history of colorectal cancer (CRC) and the risk of metachronous colorectal neoplasia (CRN) following polypectomy remains unknown. We aimed to compare the risk of metachronous CRN according to CRC family history in groups of patients aged < 50 and ≥ 50 years. METHODS: We studied patients who underwent ≥ 1 adenoma removal between 2010 and 2014 and follow-up surveillance colonoscopic examinations until 2017. RESULTS: Among the 9866 patients studied, 544 (5.5%) had ≥ 1 first-degree relatives (FDRs) affected by CRC. In patients aged < 50 years (n = 7787), as compared with having no family history of CRC, a positive family history in any FDR (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.16-1.62), a father (HR 1.35, 95% CI 1.09-1.68), or a mother (HR 1.32, 95% CI 1.005-1.74) was associated with an increased risk of metachronous CRN after adjusting for confounding factors. However, in patients aged ≥ 50 years (n = 2079), there was no significant association between having an FDR with CRC and the risk of metachronous CRN. For metachronous advanced CRN, the association between its risk and family history of CRC was not observed in either the < 50 years or ≥ 50 years of age group. CONCLUSIONS: Having an FDR with CRC at a young age (< 50 years) appears to be closely related to the risk of metachronous CRN. However, considering that the risk of metachronous advanced CRN did not depend on CRC family history, the interval of post-polypectomy surveillance colonoscopy may not need to be adjusted depending on CRC family history.


Assuntos
Pólipos Adenomatosos/cirurgia , Colectomia/efeitos adversos , Pólipos do Colo/cirurgia , Neoplasias Colorretais/cirurgia , Segunda Neoplasia Primária/genética , Pólipos Adenomatosos/epidemiologia , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patologia , Adulto , Fatores Etários , Pólipos do Colo/epidemiologia , Pólipos do Colo/genética , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/patologia , Linhagem , República da Coreia/epidemiologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
11.
Diagn Pathol ; 13(1): 88, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458818

RESUMO

BACKGROUND: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. METHODS: We performed immunostaining for ß-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. RESULTS: Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear ß-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. CONCLUSIONS: SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/ß-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.


Assuntos
Adenocarcinoma , Pólipos Adenomatosos , Biomarcadores Tumorais , Pólipos do Colo , Neoplasias Colorretais , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Imuno-Histoquímica , Instabilidade de Microssatélites , Mutação , Adenocarcinoma/química , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Pólipos Adenomatosos/química , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patologia , Pólipos Adenomatosos/cirurgia , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Pólipos do Colo/química , Pólipos do Colo/genética , Pólipos do Colo/patologia , Pólipos do Colo/cirurgia , Neoplasias Colorretais/química , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Valor Preditivo dos Testes
12.
Dis Colon Rectum ; 61(12): 1380-1385, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30346367

RESUMO

BACKGROUND: Sessile serrated adenomas/polyps are potentially premalignant colorectal lesions that are precursors to colorectal cancer arising via CpG island methylator phenotype. They are caused by the combination of a BRAF mutation and promoter hypermethylation. DNA methylation is an age-dependent phenomenon in the right colon, and we would expect the occurrence and severity of serrated neoplasia to reflect this. OBJECTIVE: The purpose of this study was to document the natural history of sessile serrated adenomas/polyps, including the ages at which they appear and the ranges of their number, size, and associated lesions. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at a tertiary referral center. PATIENTS: Consecutive patients with sessile serrated adenomas/polyps removed between 2006 and 2015 were included. Patients with IBD, familial adenomatous polyposis, Lynch syndrome, serrated polyposis, and hereditary nonpolyposis colorectal cancer were excluded. MAIN OUTCOME MEASURES: Age at which polyps were first diagnosed, location and size of polyps, demographics, and family history were measured. RESULTS: A total of 440 patients had 668 sessile serrated adenomas/polyps, 257 (58%) also had ≥1 adenoma, and 28 (6%) had a history of colorectal cancer. Mean age at diagnosis was 68 ± 11 years, and 45% were men. Two hundred had had ≥1 colonoscopy before the diagnosis of the first sessile serrated adenomas/polyps. A total of 136 patients (31%) had multiple sessile serrated adenomas/polyps, including 24% synchronous and 10% metachronous. The range of total cumulative sessile serrated adenomas/polyps was from 1 to 7. A total of 554 (83%) of 668 sessile serrated adenomas/polyps were right sided; 48% were ≥1 cm diameter and 22% were >2 cm. The size of the first sessile serrated adenomas/polyps in those diagnosed under age 50 years averaged 10 mm, those between 50 and 60 years averaged 12 mm, and those between 60 and 70 years averaged 12 mm. LIMITATIONS: No measurement of methylation or BRAF mutations in polyps or normal mucosa and a lack of subclassification of hyperplastic polyps limited this study. CONCLUSIONS: The age of onset of sessile serrated adenomas/polyps varies, but the pattern is consistent with increasing methylation in the mucosa. Early negative colonoscopies predict a low risk of methylator cancers. See Video Abstract at http://links.lww.com/DCR/A736.


Assuntos
Pólipos Adenomatosos/patologia , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Neoplasias Primárias Múltiplas/patologia , Segunda Neoplasia Primária/patologia , Pólipos Adenomatosos/genética , Idade de Início , Idoso , Transformação Celular Neoplásica , Pólipos do Colo/genética , Neoplasias Colorretais/genética , Feminino , Humanos , Mucosa Intestinal , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas , Estudos Retrospectivos , Fatores de Risco , Carga Tumoral
13.
In Vivo ; 32(6): 1473-1475, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30348703

RESUMO

BACKGROUND: The finding was recently reported of clusters of colonic crypts lined with indigenous normal epithelium displaying irregular shapes underneath the adenomatous glands of conventional (tubular or villous) adenomas. These abnormal crypts were named non-dysplastic corrupted colonic crypts (NDCs). This study explored the characteristics of cell proliferation in NDCs present in a cohort of conventional adenomas. MATERIALS AND METHODS: Sections from six conventional adenomas were challenged with the proliferation marker Ki-67 (MIB1). MIB+ proliferating clusters were regarded as those exhibiting two or more adjoining MIB+ cells. RESULTS: A total of 46 (range=1-18) NDCs were found underneath the six conventional adenomas. Out of the 46 NDCs, two exhibited only one proliferative cluster/crypt, 14 NDCs two clusters/crypt, 14 three clusters/crypt and the remaining 16 NDCs more than four distinct clusters/crypt. CONCLUSION: This preliminary study showed, evidently for the first time, that multiple, apparently haphazardly distributed clusters of proliferating cells are present in NDCs. Since the Ki-67 proliferation marker only labels progenitor daughter cells generated by stem cells, each MIB+ cluster in each NDC must have been produced by a single stem cell. Consequently, individual NDCs may harbor several stem cells, a deduction that is in concert with recent studies showing that in the normal human colon, the number of stem cells per crypt is of the order of five to six, or about 5% of the cell population of a single crypt.


Assuntos
Adenoma/patologia , Transformação Celular Neoplásica/genética , Neoplasias do Colo/patologia , Antígeno Ki-67/genética , Adenoma/genética , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/patologia , Linhagem da Célula/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Colo/patologia , Neoplasias do Colo/genética , Epitélio/patologia , Humanos , Células-Tronco Neoplásicas/patologia
14.
World J Gastroenterol ; 24(38): 4412-4418, 2018 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-30344425

RESUMO

Gastric polyposis is a rare disease. Not all polyps progress to cancer. Monoallelic mutation in Fanconi anemia (FA) genes, unlike biallelic gene mutations that causes typical FA phenotype, can increase risks of cancers in a sporadic manner. Aberrations in the FA pathway were reported in all molecular subtypes of gastric cancer. We studied a patient with synchronous gastric cancer from gastric polyposis by conducting a 13-year long-term follow up. Via pathway-driven massive parallel genomic sequencing, a germline mutation at FANCA D1359Y was identified. We identified several recurrent mutations in DNA methylation (TET1, V873I), the ß-catenin pathway (CTNNB1, S45F) and RHO signaling pathway (PLEKHG5, R203C) by comparing the genetic events between benign and malignant gastric polyps. Furthermore, we revealed gastric polyposis susceptible genes and genetic events promoting malignant transformation using pathway-driven targeted gene sequencing.


Assuntos
Pólipos Adenomatosos/genética , Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Predisposição Genética para Doença , Neoplasias do Jejuno/genética , Neoplasias Gástricas/genética , Pólipos Adenomatosos/complicações , Pólipos Adenomatosos/diagnóstico por imagem , Pólipos Adenomatosos/patologia , Idoso , Anemia Ferropriva/etiologia , Biópsia , Análise Mutacional de DNA , Gastrectomia , Hemorragia Gastrointestinal/etiologia , Gastroscopia , Humanos , Neoplasias do Jejuno/diagnóstico por imagem , Neoplasias do Jejuno/patologia , Neoplasias do Jejuno/cirurgia , Jejuno/diagnóstico por imagem , Jejuno/patologia , Jejuno/cirurgia , Masculino , Mutação , Estômago/diagnóstico por imagem , Estômago/patologia , Estômago/cirurgia , Neoplasias Gástricas/complicações , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tomografia Computadorizada por Raios X
15.
Sci Rep ; 8(1): 13974, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228361

RESUMO

The human intestine retains a complex microbial ecosystem, which performs crucial functions that impact on host health. Several studies have indicated that intestinal dysbiosis may impact on the establishment of life-threatening intestinal diseases such as colorectal cancer. An adenomatous polyp is the result of abnormal tissue growth, which is benign but is considered to be associated with a high risk of developing colorectal cancer, based on its grade of dysplasia. Development of diagnostic tools that are based on surveying the gut microbiota and are aimed at early detection of colorectal cancer represent highly desirable target. For this purpose, we performed a pilot study in which we applied a metataxonomic analysis based on 16S rRNA gene sequencing approach to unveil the composition of microbial communities of intestinal polyps. Moreover, we performed a meta-analysis involving the reconstructed microbiota composition of adenomatous polyps and publicly available metagenomics datasets of colorectal cancer. These analyses allowed the identification of microbial taxa such as Faecalibacterium, Bacteroides and Romboutsia, which appear to be depleted in cancerogenic mucosa as well as in adenomatous polyps, thus representing novel microbial biomarkers associated with early tumor formation. Furthermore, an absolute quantification of Fusubacterium nucleatum in polyps further compounded the important role of this microorganism as a valuable putative microbial biomarker for early diagnosis of colorectal cancer.


Assuntos
Pólipos Adenomatosos/diagnóstico , Bactérias/classificação , Biomarcadores/análise , Neoplasias Colorretais/diagnóstico , Pólipos Intestinais/diagnóstico , Microbiota/genética , Membrana Mucosa/metabolismo , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/microbiologia , Idoso , Bactérias/genética , Bactérias/isolamento & purificação , Neoplasias Colorretais/genética , Neoplasias Colorretais/microbiologia , Feminino , Microbioma Gastrointestinal , Humanos , Pólipos Intestinais/genética , Pólipos Intestinais/microbiologia , Masculino , Metagenômica , Membrana Mucosa/microbiologia , Projetos Piloto , Prognóstico , RNA Ribossômico 16S/genética
16.
Eur J Gastroenterol Hepatol ; 30(11): 1337-1343, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30085964

RESUMO

AIM: The risk of presenting synchronous or metachronous neoplasm, either adenoma or carcinoma, increases after an initial colonic lesion develops. It is known as tumor multicentricity and constitutes the rationale for surveillance programs. This study was designed to identify the clinical, pathologic, and molecular features related to previous or synchronous colorectal cancer (CRC) in patients with advanced adenomas (AA) or serrated polyps (SP). PATIENTS AND METHODS: We carried out a prospective analysis of 4143 colonoscopies performed at our medical department between 1 September 2014 and 30 September 2015. Patients with AA/SP associated with previous or synchronous CRC are compared with patients with solitary AA/SP. We also performed immunohistochemical for the mismatch repair proteins in 120 AA or SP, 60 of them related to CRC. RESULTS: Three-hundred and seventy-nine AA or SP were removed. Among these, 66 (17.3%) were associated with a previous (n=31) or synchronous CRC (n=35). Age older than or equal to 65 years (odds ratio: 1.15, 95% confidence interval: 1.05-1.26, P=0.002) and male sex (odds ratio: 2.13, 95% confidence interval: 1.3-3.49, P=0.003) were found to be independent predictive factors for CRC in patients with AA/SP by multivariate analysis. Only one of the 120 AA/SP available for immunohistochemical testing showed loss of staining and it was not related to CRC. CONCLUSION: In patients with AA or SP, it is possible to identify a subgroup that is more likely to be associated with CRC and then prone to tumor multicentricity. These results have potential implications for establishing criteria for a more targeted surveillance.


Assuntos
Pólipos Adenomatosos/patologia , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer/métodos , Neoplasias Primárias Múltiplas/patologia , Segunda Neoplasia Primária/patologia , Pólipos Adenomatosos/química , Pólipos Adenomatosos/genética , Pólipos Adenomatosos/cirurgia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Pólipos do Colo/química , Pólipos do Colo/genética , Pólipos do Colo/cirurgia , Neoplasias Colorretais/química , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/cirurgia , Segunda Neoplasia Primária/química , Segunda Neoplasia Primária/genética , Segunda Neoplasia Primária/cirurgia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Espanha
17.
Science ; 361(6400): 406-411, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30049881

RESUMO

Germline mutations in STK11, which encodes the tumor suppressor liver kinase B1 (LKB1), promote Peutz-Jeghers syndrome (PJS), a cancer predisposition syndrome characterized by the development of gastrointestinal (GI) polyps. Here, we report that heterozygous deletion of Stk11 in T cells (LThet mice) is sufficient to promote GI polyposis. Polyps from LThet mice, Stk11+/- mice, and human PJS patients display hallmarks of chronic inflammation, marked by inflammatory immune-cell infiltration, signal transducer and activator of transcription 3 (STAT3) activation, and increased expression of inflammatory factors associated with cancer progression [interleukin 6 (IL-6), IL-11, and CXCL2]. Targeting either T cells, IL-6, or STAT3 signaling reduced polyp growth in Stk11+/- animals. Our results identify LKB1-mediated inflammation as a tissue-extrinsic regulator of intestinal polyposis in PJS, suggesting possible therapeutic approaches by targeting deregulated inflammation in this disease.


Assuntos
Pólipos Adenomatosos/genética , Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases/genética , Neoplasias Gástricas/genética , Linfócitos T/imunologia , Pólipos Adenomatosos/imunologia , Pólipos Adenomatosos/patologia , Animais , Quimiocina CXCL2/genética , Deleção de Genes , Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-11/genética , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Síndrome de Peutz-Jeghers/imunologia , Síndrome de Peutz-Jeghers/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia
19.
Dig Dis Sci ; 63(7): 1920-1928, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29546645

RESUMO

BACKGROUND: Colorectal serrated lesions (SLs) are important premalignant lesions whose clinical and biological features are not fully understood. AIMS: We aimed to establish accurate colonoscopic diagnosis and treatment of SLs through evaluation of associations among the morphological, pathological, and molecular characteristics of SLs. METHODS: A total of 388 premalignant and 18 malignant colorectal lesions were studied. Using magnifying colonoscopy, microsurface structures were assessed based on Kudo's pit pattern classification system, and the Type II pit pattern was subcategorized into classical Type II, Type II-Open (Type II-O) and Type II-Long (Type II-L). BRAF/KRAS mutations and DNA methylation of CpG island methylator phenotype (CIMP) markers (MINT1, - 2, - 12, - 31, p16, and MLH1) were analyzed through pyrosequencing. RESULTS: Type II-O was tightly associated with sessile serrated adenoma/polyps (SSA/Ps) with BRAF mutation and CIMP-high. Most lesions with simple Type II or Type II-L were hyperplastic polyps, while mixtures of Type II or Type II-L plus more advanced pit patterns (III/IV) were characteristic of traditional serrated adenomas (TSAs). Type II-positive TSAs frequently exhibited BRAF mutation and CIMP-low, while Type II-L-positive TSAs were tightly associated with KRAS mutation and CIMP-low. Analysis of lesions containing both premalignant and cancerous components suggested Type II-L-positive TSAs may develop into KRAS-mutated/CIMP-low/microsatellite stable cancers, while Type II-O-positive SSA/Ps develop into BRAF-mutated/CIMP-high/microsatellite unstable cancers. CONCLUSIONS: These results suggest that Type II subtypes reflect distinct molecular subclasses in the serrated neoplasia pathway and that they could be useful hallmarks for identifying SLs at high risk of developing into CRC.


Assuntos
Pólipos Adenomatosos/genética , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Pólipos do Colo/genética , Neoplasias Colorretais/genética , Lesões Pré-Cancerosas/genética , Pólipos Adenomatosos/classificação , Pólipos Adenomatosos/patologia , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/patologia , Pólipos do Colo/classificação , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/classificação , Neoplasias Colorretais/patologia , Ilhas de CpG , Metilação de DNA , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Lesões Pré-Cancerosas/classificação , Lesões Pré-Cancerosas/patologia
20.
PLoS One ; 13(3): e0192499, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29590112

RESUMO

BACKGROUND: Sessile serrated polyps (SSPs) have emerged as important precursors for a large number of sporadic colorectal cancers. They are difficult to detect during colonoscopy due to their flat shape and the excessive amounts of secreted mucin that cover the polyps. The underlying genetic and epigenetic basis for the emergence of SSPs is largely unknown with existing genetic studies confined to a limited number of oncogenes and tumor suppressors. A full characterization of the genetic and epigenetic landscape of SSPs would provide insight into their origin and potentially offer new biomarkers useful for detection of SSPs in stool samples. METHODS: We used a combination of genome-wide mutation detection, exome sequencing and DNA methylation profiling (via methyl-array and whole-genome bisulfite sequencing) to analyze multiple samples of sessile serrated polyps and compared these to familial adenomatous polyps. RESULTS: Our analysis revealed BRAF-V600E as the sole recurring somatic mutation in SSPs with no additional major genetic mutations detected. The occurrence of BRAF-V600E was coincident with a unique DNA methylation pattern revealing a set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples. These methylation patterns effectively distinguished sessile serrated polys from adenomatous polyps and did so more effectively than parallel gene expression profiles. CONCLUSIONS: This study provides an important example of a single oncogenic mutation leading to reproducible global DNA methylation changes. These methylated markers are specific to SSPs and could be of important clinical relevance for the early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing.


Assuntos
Pólipos Adenomatosos/genética , Pólipos do Colo/genética , Metilação de DNA , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Pólipos Adenomatosos/patologia , Pólipos do Colo/patologia , Ilhas de CpG/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Recidiva Local de Neoplasia , Sequenciamento Completo do Genoma/métodos
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