Alterations in APC, BECN1, and TP53 gene expression levels in colon cancer cells caused by monosodium glutamate / Alterações nos níveis de expressão gênica APC, BECN1 e TP53 em células de câncer de cólon causadas por glutamato monossódico

Colorectal cancer (CRC) is a disease with high incidence worldwide. As of 2018, it is the second leading cause of cancer deaths in the world. In Saudi Arabia, the incidence of this disease has been increasing in the younger population. Both genetic and lifestyle factors may have contributed to its increased incidence and pathogenesis. Monosodium glutamate (MSG) is a food flavor enhancer that can be found in many commercial foods, and it can sometimes be used as a substitute to table salt. MSG has been investigated for its possible genotoxicity, yielding controversial results. In the present study, the effect of MSG on cell viability and its effect on expression of APC, BECN1, and TP53 genes in SW620 and SW480 colon cancer cell lines were studied. TP53 is a tumor suppressor gene that functions in modifying DNA errors and/or inducing apoptosis of damaged cells, and both APC and BECN1 genes are involved in CRC and are of importance in cellular growth and metastasis. Cancer cell viability was analyzed using MTT assay, and the results showed a significant increase in the number of viable cells after 24h of treatment with MSG with different concentrations (0.5, 1.0, 10, 50, and 100mM). Moreover, gene expression results showed a significant increase in the expression levels of APC and BECN1 under specified conditions in both cell lines; conversely, TP53 showed a significant decrease in expression in SW620 cells. Thus, it can be concluded that MSG possibly confers a pro-proliferative effect on CRC cells.

O câncer colorretal (CCR) é uma doença com alta incidência mundial. Desde 2018, é a segunda principal causa de mortes por câncer no mundo. Na Arábia Saudita, a incidência dessa doença vem aumentando na população mais jovem. Tanto fatores genéticos quanto de estilo de vida podem ter contribuído para o aumento da sua incidência e patogênese. O glutamato monossódico (MSG) é um intensificador de sabor de alimentos que pode ser encontrado em muitos alimentos comerciais e às vezes pode ser usado como um substituto do sal de cozinha. O MSG tem sido investigado por sua possível genotoxicidade, produzindo resultados controversos. Neste estudo, foram estudados o efeito do MSG na viabilidade celular e seu efeito na expressão dos genes APC, BECN1 e TP53 em linhas de células de câncer de cólon SW620 e SW480. TP53 é um gene supressor de tumor que atua modificando erros de DNA e/ou induzindo apoptose de células danificadas, estando os genes APC e BECN1 envolvidos no CRC e sendo importantes no crescimento celular e metástase. A viabilidade das células cancerosas foi analisada por meio do ensaio MTT, e os resultados mostraram um aumento significativo no número de células viáveis após 24 h de tratamento com MSG em diferentes concentrações (0,5; 1,0; 10; 50 e 100mM). Além disso, os resultados da expressão gênica mostraram um aumento significativo nos níveis de expressão de APC e BECN1 sob condições especificadas em ambas as linhagens celulares. Por outro lado, TP53 mostrou uma diminuição significativa na expressão em células SW620. Assim, pode-se concluir que, possivelmente, o MSG confere um efeito pró-proliferativo às células CRC.

Analysis of APC gene variants in a pedigree affected with familial adenomatous polyposis / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with familial adenomatous polyposis (FAP).@*METHODS@#The proband, with recurrence of blood in the stool, was diagnosed with FAP by endoscopy, pathological examination and a family history. She was subjected to next generation sequencing to detect genetic variant. Suspected variant was verified by Sanger sequencing of members from her pedigree.@*RESULTS@#The proband, her mother and brother were found to carry a heterozygous c.532-1G>A variant of the APC gene, which may lead to aberrant splicing of mRNA resulting in a truncated protein, which may lose its normal function and promote the tumorigenesis. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.532-1G>A variant of APC gene was predicted to be pathogenic(PVS1+PP1+PP4+PP5).@*CONCLUSION@#The c.532-1G>A variant of the APC gene probably underlay the pathogenesis of FAP in this pedigree.

Revisión: Factores asociados a cáncer colorrectal / Review: Associated factors with colorectal cancer

Resumen Introducción: El cáncer colorrectal (CCR) es la neoplasia de mayor frecuencia en vías digestivas, constituyendo del 9 al 10% de todos los cánceres en el mundo. Se considera que es multicausal, pues abarca factores intrínsecos del huésped como mutaciones genéticas, hormonales y condiciones inmunológicas; además de factores externos como dietas poco saludables, consumo de alcohol, obesidad, sedentarismo, tabaquismo y la exposición ambiental a carcinógenos. Las manifestaciones clínicas son poco específicas, razón por la cual el diagnóstico está enfocado en grupos de riesgo relacionados con la edad e historia familiar demostrada. Objetivo: Identificar los factores genéticos y de estilos de vida predisponentes al desarrollo de CCR. Metodología: Se realizó una búsqueda de la bibliografía respectiva en las bases de datos ScienceDirect, Google académico, Redalyc, Scielo, Proquest publicada durante el período 2004- 2019, mediante las palabras clave: Colorrectal cancer, risk factors, epidemiology, mortality, mutation, incidence. Resultados: Se observaron factores genéticos predisponentes entre un 20% a 25% de las personas con CCR asociados principalmente con la mutación de gen APC. En relación al cáncer esporádico, se identifica hasta en un 80% de los casos, relacionado con el consumo no controlado de alimentos como carnes rojas, embutidos, café, además de hábitos como el consumo de cigarrillo y alcohol conjuntamente con el estrés y comorbilidades como la obesidad y la diabetes. Conclusión: La multicausalidad del CCR está centrada en factores tanto internos como externos siendo de relevancia el seguimiento para personas genéticamente predispuestas y la implementación de estilos de vida saludables que reduzcan la mortalidad por esta causa.

Abstract Introduction: Colorectal cancer (CRC) is the most frequent neoplasm in the digestive tract; it constitutes 9 of 10% of all cancer cases in the world. This type of cancer is considered multicausal since it is associated with intrinsic and extrinsic factors. Among the internal factors, there are genetic, hormonal mutations, and immunological conditions. On the other hand, the external factors are composed of unhealthy diets, alcohol consumption, obesity, sedentary lifestyle, smoking habits, and environmental exposure to carcinogens. The clinical symptoms are not very specific; that is why the diagnosis is focused on risk groups related to age and proven family medical history. Objective: To identify genetic factors and lifestyle factors related to the development of Colorectal cancer (CRC). Methodology: A literature search was carried out in databases such as ScienceDirect, Google Scholar, Redalyc, Scielo, Proquest, in a range of time between 2004 and 2019. The keywords: colorectal cancer, risk factors, epidemiology, mortality, mutation, and incidence were used as helpers for the search. Results: Predisposing genetic factors were observed in about 20% to 25% of people with CRC associated primarily with the APC gene mutation. In terms of sporadic cancer, the results showed that 80% of the cases were related to the uncontrolled consumption of red meat, sausages, and coffee. Additionally, smoking and alcoholic behaviors, stress, and comorbidities, such as obesity and diabetes, were also the cause of the development of this issue. Conclusion: CRC could be caused by internal and external factors. Based on this, the people with a genetic predisposition to this issue should monitor themselves frequently and implement a healthy lifestyle that reduces the probability of suffering from this type of cancer.

The fluctuation of APC gene in WNT signaling with adenine deletion of adenomatous polyposis coli, is associated in colorectal cancer / A flutuação do gene da APC na via de sinalização WNT com deleção de adenina na polipose adenomatosa do cólon está associada ao câncer colorretal

ABSTRACT Colorectal cancer is one of the most important malignancies in the classification of gastrointestinal cancers. One of the predisposing factors at molecular level for this cancer is via WNT signaling which is associated with the vast numbers of different genes. Thus, in this study, we aimed to investigate whether Adenomatous Polyposis Coli gene (APC) mutation of rs41115in two locations such as 132.002 and 131.989 acts as a trigger or cause of colorectal cancer. Relatively, 30 blood samples of colorectal cancer patients and 30 normal blood samples as control group after colonoscopy and also confirmation of pathology report at Rohani Hospital in Babol (Iran) were investigated. The primers were designed in order to be included the rs41115 to identify the particular polymorphisms of gene. The polymerase chain reaction (PCR direct sequencing method) was used. Conclusively, deletion of adenine in two specific locations such as 131.989 and 132.002 has been identified, but there was no relationship between rs41115 polymorphisms located in adenomatous polyposis coli gene and colorectal cancer.

RESUMO O câncer colorretal é uma das neoplasias malignas mais importantes na classificação dos cânceres gastrointestinais. Um dos fatores predisponentes no âmbito molecular para esse câncer é através da via de sinalização WNT, que está associada a um grande número de genes diferentes. Portanto, neste estudo, objetivamos investigar se a mutação rs41115 do gene da polipose adenomatosa do cólon (Adenomatous Polyposis Coli - APC) em dois locais como 132.002 e 131.989 atua como gatilho ou como causa do câncer colorretal. Relativamente, 30 amostras de sangue de pacientes com câncer colorretal e 30 amostras de sangue normal (grupo controle) foram analisadas após a colonoscopia, bem como a confirmação do laudo da patologia no Rohani Hospital em Babol (Irã). Os primers foram projetados de modo a incluir o rs41115 para identificar os polimorfismos particulares do gene. A reação em cadeia da polimerase (método de sequenciamento direto por PCR) foi utilizada. Conclusivamente, a deleção de adenina em dois locais específicos, como 131.989 e 132.002, foi identificada, mas não houve relação entre o polimorfismo rs41115 localizado no gene da polipose adenomatosa do cólon e o câncer colorretal.

A Novel Adenomatous Polyposis Coli Gene Mutation of Cribriform-Morular Variant Papillary Thyroid Carcinoma: A Case Report / 대한이비인후과학회지

Cribriform-morular variant papillary thyroid carcinoma (CMV-PTC) is a rare cancer that may arise in patients with familial adenomatous polyposis (FAP). Adenomatous polyposis coli (APC) gene mutation is associated with FAP, which is known as a premalignant lesion of colon cancer. In this report, we report a 16 years old patient of CMV-PTC comorbid with FAP, which was related with a new type of APC gene mutation.

Advance in research on the correlation between genotypes of susceptible mutations and clinical phenotype of familial adenomatous polyposis / 中华医学遗传学杂志

Familial adenomatous polyposis (FAP) is one of the most common hereditary colorectal cancers. Its intestinal and extra-intestinal manifestations are correlated with mutation sties of the APC gene. Potential gene modulation sites in patients who have typical clinical manifestations but with unidentified APC mutations are also discussed, which included MUTYH gene, AXIN gene and certain epigenetic changes. With the generalization of Precision Medicine, to offer individualized treatment and surveillance strategy based on the genotype-phenotype correlation will be of great value for FAP patients. This review focuses on the research advance in genotype - phenotype correlation studies of FAP patients.

Exome sequence analysis of Kaposiform hemangioendothelioma: identification of putative driver mutations

Abstract BACKGROUND: Kaposiform hemangioendothelioma is a rare, intermediate, malignant tumor. The tumor's etiology remains unknown and there are no specific treatments. OBJECTIVE: In this study, we performed exome sequencing using DNA from a Kaposiform hemangioendothelioma patient, and found putative candidates for the responsible mutations. METHOD: The genomic DNA for exome sequencing was obtained from the tumor tissue and matched normal tissue from the same individual. Exome sequencing was performed on HiSeq2000 sequencer platform. RESULTS: Among oncogenes, germline missense single nucleotide variants were observed in the TP53 and APC genes in both the tumor and normal tissue. As tumor-specific somatic mutations, we identified 81 candidate genes, including 4 nonsense changes, 68 missense changes and 9 insertions/deletions. The mutations in ITGB2, IL-32 and DIDO1 were included in them. CONCLUSION: This is a pilot study, and future analysis with more patients is needed to clarify: the detailed pathogenesis of this tumor, the novel diagnostic methods by detecting specific mutations, and the new therapeutic strategies targeting the mutation.

Clinical and molecular characteristics of a child with familial adenomatous polyposis / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore the clinical features and molecular mutation of early-onset familial adenomatous polyposis(FAP) in childhood.</p><p><b>METHOD</b>The clinical features, endoscopic findings, pathology and therapeutic effect of sulindac during 11 years follow-up in a child with FAP were retrospectively reviewed . Adenomatous polyposis coli (APC) gene mutation analysis was performed by PCR and first generation sequencing.</p><p><b>RESULT</b>This 6-year-old girl was admitted for intermittent bloody stool during the last one and a half years. Colonoscopy showed hundreds of polyps in the rectum and colon. Pathological examination revealed tubular adenomas with high grade dysplasia. During the follow-up period of 11 years, the child presented intermittent mucous bloody stool. Endoscopy showed the number of polyps in colon and rectum increased to thousands, and found multiple polyps in gastric fundus and body.She was treated with sulindac at the age of 13. Then the number of polyps and the grade of pathology showed a slight improvement and no carcinoma was seen on biopsy. She has not accepted surgery until now. Gene sequencing of this child revealed 5 bp deletion at codon 1,309 of exon 15 (c.3927_3931delAAAGA) of tumor suppressor gene, whereas none of her parents had the same mutation. And no polyps were found on her parents colonoscopy.</p><p><b>CONCLUSION</b>This child with FAP had an early onset of this disease, and clinical conditions were exacerbated with age. Sulindac was partially effective in controlling size and number of polyps. The site of mutation in this case was consistent with classic FAP, and without family history, the mutation may be a sporadic one.</p>

A Novel Germline Mutation of the APC Gene: A Case Report of Familial Adenomatous Polyposis Requiring Repeated Endoscopic Resections for Gastroduodenal Polyps

Familial adenomatous polyposis (FAP) is a precancerous clinical entity, which is characterized by the development of numerous adenomatous polyps throughout the colon and rectum. The majority of FAP are associated with mutations of the adenomatous polyposis coli (APC) gene. Until now, more than 1,000 different APC mutations have been reported and some mutations express attenuated phenotypes which are milder forms with 10~100 colorectal polyps. We identified a novel mutation of APC gene which expressed an attenuated FAP but caused large gastroduodenal tubular adenomas requiring repeated endoscopic resections. A 16-year-old girl was referred to Incheon St. Mary's Hospital for evaluation of gastric polyposis. Initial esophagogastroduodenoscopy (EGD) showed numerous gastric polyps in the fundus and upper body and a few polyps in the duodenum. Pathologic examination confirmed gastric polyps as fundic gland polyps and duodenal polyps as tubular adenomas. Only a few colonic polyps of 2 to 5 mm in size were found on colonoscopy. Genetic analysis using polymerase chain reaction and direct sequencing revealed a novel stop codon mutation at codon 1522 in exon 16 of APC gene. At 12-month, 18-month, and 35-month follow-up EGD, large duodenal polyp and gastric polyps were removed endoscopically.

Risk Factors for Metachronous Gastric Neoplasms in Patients Who Underwent Endoscopic Resection of a Gastric Neoplasm

BACKGROUND/AIMS: To identify the risk factors for metachronous gastric neoplasms in patients who underwent an endoscopic resection of a gastric neoplasm. METHODS: We prospectively collected clinicopathologic data and measured the methylation levels of HAND1, THBD, APC, and MOS in the gastric mucosa by methylation-specific real-time polymerase chain reaction in patients who underwent endoscopic resection of gastric neoplasms. RESULTS: A total of 257 patients with gastric neoplasms (113 low-grade dysplasias, 25 high-grade dysplasias, and 119 early gastric cancers) were enrolled. Metachronous gastric neoplasm developed in 7.4% of patients during a mean follow-up of 52 months. The 5-year cumulative incidence of metachronous gastric neoplasm was 4.8%. Multivariate analysis showed that moderate/severe corpus intestinal metaplasia and family history of gastric cancer were independent risk factors for metachronous gastric neoplasm development; the hazard ratios were 4.12 (95% confidence interval [CI], 1.23 to 13.87; p=0.022) and 3.52 (95% CI, 1.09 to 11.40; p=0.036), respectively. The methylation level of MOS was significantly elevated in patients with metachronous gastric neoplasms compared age- and sex-matched patients without metachronous gastric neoplasms (p=0.020). CONCLUSIONS: In patients who underwent endoscopic resection of gastric neoplasms, moderate/severe corpus intestinal metaplasia and a family history of gastric cancer were independent risk factors for metachronous gastric neoplasm, and MOS was significantly hypermethylated in patients with metachronous gastric neoplasms.

unique profile of adenomatous polyposis coli gene mutations in iranian patients suffering sporadic colorectal cancer

Colorectal cancer [CRC] is one of the most common and aggressive cancers worldwide. The majority of CRC cases are sporadic that caused by somatic mutations. The Adenomatous Polyposis Coli [APC; OMIM 611731] is a tumor suppressor gene of Wnt pathway and is frequently mutated in CRC cases. This study was designed to investigate the spectrum of APC gene mutations in Iranian patients with sporadic colorectal cancer. In this descriptive study, Tumor and normal tissue samples were obtained from thirty randomly selected and unrelated sporadic CRC patients. We examined the hotspot region of the APC gene in all patients. Our mutation detection method was direct DNA sequencing. We found a total of 8 different APC mutations, including two nonsense mutations [c.4099C>T and c.4348C>T], two missense mutations [c.3236C>G and c.3527C>T] and four frame shift mutations [c.2804dupA, c.4317delT, c.4464_4471delATTACATT and c.4468_4469dupCA]. The c.3236C>G and c.4468_4469dupCA are novel mutations. The overall frequency of APC mutation was 26.7% [8 of 30 patients]. This mutation rate is lower in comparison with previous studies from other countries. The findings of present study demonstrate a different APC mutation spectrum in CRC patients of Iranian origin compared with other populations

Identificação de mutações nos genes APC e MUTYH em famílias com polipose adenomatosa intestinal / Mutational screening of APC and MUTYH genes in families with adenomatous polyposis

Atualmente, pacientes com múltiplos adenomas colorretais são avaliados para mutações germinativas em dois genes, APC e MUTYH. Pacientes com mutações em APC apresentam Polipose Adenomatosa Familiar Clássica ou Atenuada (FAP/AFAP), enquanto que pacientes portadores de mutações bialélicas em MUTYH apresentam Polipose Associada ao MUTYH (MAP). O espectro das mutações em APC e MUTYH, assim como as correlações genótipo-fenótipo nestas síndromes, apresentam importante impacto clínico e podem ser distintas em cada população, tornando necessária a obtenção de dados genéticos e clínicos de diferentes populações. Além disso, cerca de 10-15% dos pacientes com polipose não apresentam mutações nesses genes, o que sugere a existência de outros genes de predisposição ainda desconhecidos. Assim, os objetivos deste estudo foram caracterizar mutações germinativas nos genes APC e MUTYH em pacientes Brasileiros com polipose, além de identificar novos genes associados com a síndrome através de sequenciamento de exoma dos pacientes negativos. No total, 23 pacientes não relacionados foram avaliados para mutações pontuais na região codificante dos genes APC e MUTYH através de sequenciamento capilar, e para rearranjos genômicos nos mesmos genes por meio de MLPA (Multiplex Ligation-Dependent Probe Amplification), arrays de hibridação genômica comparativa (CGH-array), e PCR duplex quantitativo. Este último método de avaliação do número de cópias genômicas foi desenvolvido e validado no presente estudo. Foram identificados 21 pacientes mutados nesta coorte (91%) - 6 pacientes apresentaram mutações patogênicas em MUTYH, 14 apresentaram mutações patogênicas em APC e um paciente foi portador de uma nova variante missense de significado clínico desconhecido em APC (p.Val1789Leu); seis mutações foram descritas pela primeira vez neste trabalho. Em um destes pacientes identificamos a primeira grande deleção genômica descrita no gene MUTYH. Correlações genótipo-fenótipo dos dados...

Patients with multiple colorectal adenomas are currently screened for germline mutations in two genes, APC and MUTYH. APC-mutated patients present classic or attenuated familial adenomatous polyposis (FAP/ AFAP), while patients carrying biallelic MUTYH mutations exhibit MUTYH-associated polyposis (MAP). The spectrum of APC and MUTYH mutations as well as the genotype-phenotype correlations in polyposis syndromes present clinical impact and can be population specific, making important to obtain genetic and clinical data from different populations. Furthermore, up to 10-15% of polyposis patients do not harbor mutations in these genes, suggesting that other yet unknown polyposis-predisposing genes could exist. Thus, the aim of this study was to characterize germline mutations in APC and MUTYH genes in Brazilian polyposis and to investigate novel susceptibility genes by exome sequencing of negative patients. At total, 23 unrelated polyposis patients were screened for APC/MUTYH point mutations through DNA capillary sequencing, and for APC and MUTYH genomic rearrangements through MLPA (multiplex ligation-dependent probe amplification), array-comparative genomic hybridization, and duplex quantitative PCR. This last gene dosage method was developed and validated in this study. We identified 21 mutated patients in this cohort (91%) – 6 patients carried MUTYH pathogenic mutations, 14 carried APC pathogenic mutations and one carried a novel APC missense variant of unknown clinical significance (p.Val1789Leu); six mutations were described for the first time in this series. One of these patients harbored the first large genomic deletion identified in MUTYH gene...

APC protein immunoexpression in colorectal adenoma and adenocarcinoma / Imunoexpressão da proteína APC nos tecidos de adenoma e de adenocarcinoma colorretais

BACKGROUND: activation of the Wnt pathway by mutated APC gene is considered the initial event in colorectal carcinogenesis. The identification of these mutations can improve the specific treatment of the adenocarcinoma. OBJECTIVE: detect and evaluate wild-type APC protein in tissue from colorectal adenoma, adenocarcinoma and adjacent mucosa. METHODS: 42 patients that underwent surgery for adenocarcinoma and 53 patients with resected adenomas were studied. Tissue samples from the adenocarcinoma were obtained from the tumor and from adjacent non-neoplastic mucosa located 10 cm from the proximal margin of the tumor. Adenoma tissue was obtained from representative areas. Blocks of tissue microarray (TMA) were submitted to immunohistochemistry with anti-APC, with readings of positivity and intensity of immunostaining and the score of immune expression of APC protein was obtained. RESULTS: the APC protein immune expression score showed a significantly lower expression of APC protein in the adenoma when compared with the adenocarcinoma (p < 0.0001) and adjacent mucosa (p < 0.0001). The APC protein immune expression score in the colorectal mucosa and adjacent to the adenocarcinoma showed no significant difference (p = 0.24). CONCLUSIONS: the finding of decreased expression of APC protein in adenoma tissue may indicate that the mutated APC gene may contribute to the changes in the adenoma-carcinoma process of carcinogenesis sequence. The strong expression of protein APC in tissues from the carcinoma and adjacent mucosa suggests that in most patients in this series, the mutation of the APC gene did not participate in the oncogenesis mechanism. (AU)

RACIONAL: a ativação da via Wnt pelo gene APC mutado é considerado evento inicial da carcinogênese colorretal. A identificação dessas mutações pode tornar o tratamento do adenocarcinoma mais específico. OBJETIVO: detectar e avaliar a proteína APC não mutada em tecidos de adenoma, adenocarcinoma e mucosa adjacente. MÉTODO: estudados 42 doentes operados de adenocarcinoma e 53 com adenomas ressecados. Tecidos de adenocarcinoma foram obtidas da neoplasia e da mucosa adjacente não neoplásica situadas a 10 cm da margem proximal do tumor. Tecidos do adenoma foram obtidas de área representativa. Blocos de tissue microarray (TMA) foram submetidos a imuno-histoquímica com anticorpo anti-APC. Avaliadas a positividade e intensidade da expressão e obtidos escores da imunoexpressão da proteína APC. RESULTADOS: o escore da imunoexpressão da proteína APC no adenoma foi significantemente menor do que no adenocarcinoma (p < 0,0001) e na mucosa adjacente (p < 0,0001). O escore da imunoexpressão da proteína APC na mucosa adjacente e no adenocarcinoma não mostraram diferença significante (p = 0,24). CONCLUSÕES: a menor expressão da proteína APC no adenoma pode indicar que o gene APC mutado participa das alterações do processo adenoma-carcinoma. A forte expressão da proteína APC no CCR e na mucosa adjacente sugerem que a mutação do gene APC não participou da oncogênese. (AU)

Cáncer de tiroides y síndromes polipósicos intestinales Síndrome de Gardner / Thyroid cancer and intestinal polyposis syndromes Gardner syndrome

Resumen Presentamos el caso de una mujer de 22 años de edad, evaluada debido a que en su historia familiar a su madre se le encontró carcinoma de colon sigmoide. A la paciente se le diagnosticó poliposis colónica, que resolvió tras remoción endoscópica de las lesiones. Se realizó estudio de nódulo tiroideo y se realizó tiroidectomía total encontrándose un carcinoma papilar de tiroides como diagnóstico definitivo. Hicimos una revisión de la literatura. (Acta Med Colomb 2013; 38: 182-185).

Abstract We report the case of a 22-year-old woman evaluated because in her family history his mother had a sigmoid colon carcinoma. The patient was diagnosed with colonic polyposis, which resolved after endoscopic removal of the lesions. We made the study of a thyroid nodule and performed total finding a papillary thyroid carcinoma as definitive diagnosis. (Acta Med Colomb 2013; 38: 182-185).

A Novel Germline Mutation in Exon 15 of the APC Gene in Attenuated Familial Adenomatous Polyposis: A Report of Two Cases

Attenuated familial adenomatous polyposis (AFAP) is a variant of familial adenomatous polyposis with fewer than one hundred colorectal polyps and a later age of onset of the cancer. Here, we report two cases of AFAP within family members. Each patient demonstrated the same novel germ line mutation in exon 15 of the adenomatous polyposis coli (APC) gene and was successfully managed with sulindac after refusal to perform colectomy: a 23-year-old man with incidentally diagnosed gastric adenoma and fundic gland polyps underwent colonoscopy, and fewer than 100 colorectal polyps were found; a 48-year-old woman who happened to be the mother of the 23-year-old man also showed fewer than 100 colorectal polyps on colonoscopy. Genetic analysis revealed a novel frameshift mutation in exon 15 of the APC gene. The deletion of adenine-guanine with the insertion of thymine in c.3833-3834 resulted in the formation of stop codon 1,287 in both patients. The patients were treated with sulindac due to their refusal to undergo colectomy. The annual follow-up upper endoscopy and colonoscopy in the following 2 years revealed significant regression of the colorectal polyps in both patients.

Definição do perfil de alterações das sequências dos genes APC, CTNNB1, WT1, ETX e PLCG2 em tumores de Wilms / Wilms tumor genomic re-sequencing for evaluating gene loci of WTX, WT1, CTNNB1, APC and PLCG2

O tumor de Wilms (TW) origina-se das células precursoras do rim embrionário, e já foram observados eventos comuns a ambos os processos, tumorigênese e nefrogênese. A identificação de alterações moleculares durante esses processos é crucial para entender os eventos desencadeadores do TW. O gene WT1 codifica para um fator de transcrição com expressão finamente coordenada durante o desenvolvimento do rim, e mutações nesse gene são relatadas em 10% dos TWs esporádicos. Adicionalmente, desregulação no nível de expressão ou mutações de outros genes como a CTNNB1 também sugerem uma conexão entre TW e nefrogênese. Também são encontradas mutações de WTX em alguns casos de TWs. Atualmente, acredita-se que mutações de WTX, WT1 e CTNNB1 juntas estão associadas a cerca de 30% dos TWs, sendo que mutações gênicas não foram associados para a maioria dos casos. Resultados de um projeto desenvolvido em nosso laboratório apontaram os genes APC e PLCG2 como candidatos a estarem alterados nesse tumor. Nesse estudo anterior, o APC foi observado com localização predominantemente nuclear nos TWs, semelhante aos estágios iniciais do desenvolvimento normal do rim, e diferente do rim normal, que apresenta localização citoplasmática. O PLCG2 foi associado pela primeira vez a uma doença, sendo observada a ausência de marcação proteica na maioria dos TW, semelhante aos estágios iniciais do desenvolvimento, e diferente do rim diferenciado, que apresenta alta expressão da proteína. Com o advento de técnicas modernas de sequenciamento, velozes do ponto de vista de geração de bases e relativamente baratas, tornou-se factível a avaliação de toda a região que abrange o gene a um custo e tempo relativamente baixos. Com isso torna-se viável aplicar o método de sequenciamento de alta performance para avaliação de diversos pacientes...

Poliposis adenomatosa familiar: presentación de un caso y revisión de la literatura / Familial adenomatous polyposis: case report and literature review

Colorectal cancer (CRC) is a genetic and epigenetic disease. Approximately one third of the CRC has an hereditary component. Familial adenomatous polyposis (FAP) is an autosomal dominant inherited condition that has its origins in the line of APC gene mutation, which occurs with a frequency of approximately 1:10,000 live births. We report a case of a patient of 25 years with FAP. This review provides current knowledge on the broad clinical spectrum of this disease, also referring to the optimal method of diagnosis, differential diagnosis and management.

El cáncer colorrectal (CCR) es una enfermedad genética y epigenética. Aproximadamente un tercio del CCR tiene un componente hereditario. La poliposis adenomatosa familiar (PAF) es una condición hereditaria autosómica dominante que tiene su origen en la línea de mutación del gen APC, el cual ocurre con una frecuencia aproximada de 1:10.000 nacidos vivos. Se reporta el caso de una paciente de 25 años con PAF. La presente revisión proporciona los conocimientos actuales sobre el amplio espectro clínico de esta enfermedad, refiriéndose también al método óptimo de diagnóstico, diagnóstico diferencial y su manejo.

Expression of Wnt5a, APC, β-catenin and their clinical significance in human colorectal adenocarcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the expression of Wnt5a gene mRNA and Wnt5a, APC, β-catenin proteins in human colorectal adenocarcinoma (CRC) and explore its clinical significance.</p><p><b>METHODS</b>Wnt5a mRNA level was measured in 30 patients with CRC and paired non-tumor tissues by real-time PCR. Immunohistochemical staining of Wnt5a, APC, β-catenin was performed in samples of 62 patients with CRC using SP system.</p><p><b>RESULTS</b>The relative expression level of Wnt5a mRNA in fresh CRC is 0.1232 ± 0.0140, which is significantly higher than that in adjacent colorectal mucosa (0.0497 ± 0.0074, P = 0.02). A low expression of Wnt5a protein was observed in 38 of 62 CRC. Wnt5a protein expression was closely correlated with the tumor types and the degree of tumor differentiation (P < 0.05). There was no apparent relationship with lymph node metastasis, depth of myometrial invasion and TNM stages (P > 0.05). APC protein was decreased in 38 of 62 CRC. The expression of APC was closely correlated with the tumor types (P < 0.05). There was no apparent relationship with the degree of tumor differentiation, lymph node metastasis, depth of myometrial invasion and TNM stages (P > 0.05). The expression of β-catenin was observed in cytoplasm and/or cell nuclei in 50 of 62 CRC. The positive rate of β-catenin expression was closely correlated with the degree of tumor differentiation, lymph node metastasis, depth of myometrial invasion and TNM stages (P < 0.05). There was no apparent relationship with the tumor types (P > 0.05). The expressions of Wnt5a (r = 0.271, P = 0.027) and APC (r = 0.343, P = 0.004) were correlated with that of β-catenin in CRC, respectively, but there was no correlation between the expressions of Wnt5a and APC protein (r = 0.218, P = 0.078) in the tumors.</p><p><b>CONCLUSIONS</b>Wnt5a, APC and β-catenin genes might be involved in the carcinogenesis and development of CRC. It is hypothesized that down-regulation of APC and Wnt5a proteins may be one of causes of ectopic expression of β-catenin in CRC.</p>

Adenomas aserrados: otro precursor de carcinoma de colon / Serrated adenoma: another precursor of colon cancer

En este estudio se describen 12 pacientes a quienes se le realizó Colonoscopia en el período de un año entre marzo 2009 y mayo 2010 (10/83,33% mujeres, 2/16,67% hombres) encontrándose lesiones planas, sésiles, sobre pliegues en colon derecho, patrón de Kudo I – II (criptas elongadas horizontalmente). La aplicación de la técnica de cromoscopia electrónica combinada con magnificación (FICE) constituye un área prometedora en la descripción de cambios patológicos mínimos de la mucosa y microvasculares. Permite incrementar la correlación entre las imágenes endoscópicas y los resultados histopatológicos. Los adenomas aserrados pueden constituir lesiones precursoras de carcinoma colorrectal con diferente secuencia a la clásica secuencia adenoma-carcinoma. Los estudios morfológicos y moleculares están identificando vías evolutivas relacionadas a metilación del ADN, mutación del BRAF e inestabilidad de microsatélites.

This study includes 12 consecutive patients who had a colonoscopy performed between Mar 2009 and May 2010 (10/83,33% females, 2/16,67% males), finding sessile lesion have a predilection for the proximal colon, pits patterns I – II (crypt dilatation and horizontal extension of crypts immediately above the muscularis mucosae). The application of this new technology electronic chromoendoscopy combined with high resolution endoscopy has promising areas of development in the description of pathologic mucosal changes and microvessels. This advanced technology allows an increased correlation between the images processed and the histological results. The serrated pathway neoplastic encompasses a morphologically and molecularly distinct group of colorectal neoplasms and represents an alternative molecular pathway to colorectal cancer. The sequence appears to begin with a non-dysplastic serrated polyp to a serrated adenoma and ultimately to carcinoma. Morphological and molecular studies are distinguishing a separate evolutionary pathway for colorectal cancer with extensive DNA methylation, mutation of BRAF and microsatellite instability.

Molecular Pathogenesis of Gastric Cancer

In this article, I will survey the major genetic susceptibility and somatic genetic alterations involved in gastric cancer and adenoma. These include germline and somatic genetic alterations in oncogenes, tumor suppressor genes, and apoptosis-related genes. A small proportion of gastric cancers arise as a consequence of hereditary predisposition caused by specific germline mutations in E-cadherin, mismatch repair genes, adenomatous polyposis coli, and STK11. Aberrant expression of activation induced cytidine deaminase, triggered by Helicobacter pylori infection, accumulates with genetic mutations of oncogenes and tumor suppressor genes, including p53 and CTNNB1. Inactivation of trefoil factor family 1, which is a gastric specific tumor suppressor, occurs in gastric adenomas and cancers. Ectopic expression of CDX2 leads to intestinal metaplasia and defective Cdx2 expression accelerates the transformation of metaplastic cells to gastric cancer. Genetic alterations of p53 and genes related to Wnt signaling pathway and microsatellite instability occur early in the development of gastric carcinoma, indicating that detection of certain genetic alterations in adenomas may be indicative of malignant transformation. In addition, inactivation of apoptosis-inducing gene caused by mutations may be an escaping mechanism against apoptotic cell death and contribute to the progression of gastric cancer. Although the results of many studies are contradictory with one another, genetic alterations in oncogenes and tumor suppressor genes are present even in gastric adenoma and increase in frequency during multistep gastric carcinogenesis. Genetic alterations described herein, and from as yet unidentified target genes in gastric cancer cells, will guide us towards more effective risk assessment, diagnosis, and treatment.