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1.
Eur J Med Genet ; 68: 104913, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38286305

RESUMO

BACKGROUND: Familial Adenomatous Polyposis (FAP) is a colorectal cancer (CRC) predisposition syndrome caused by germline APC mutations and characterised by an increased risk of CRC and colonic polyps and, in certain forms, of specific prominent extraintestinal manifestations, namely osteomas, soft tissue tumours and dental anomalies. Pachydysostosis of the fibula is a rare clinical entity defined by unilateral bowing of the distal portion of the fibula and elongation of the entire bone, without affectation of the tibia. CLINICAL REPORT: We report a 17-year-old male, who presented with a non-progressive bowing of the right leg detected at 18 months of age caused by a fibula malformation (later characterized as pachydysostosis) and a large exophytic osteoma of the left radius, noticed at the age of 15 years, without gastrointestinal symptoms. There was no relevant family history. Detailed characterisation revealed multiple osteomas, skin lesions and dental abnormalities, raising the hypothesis of FAP. This diagnosis was confirmed by genetic testing [c.4406_4409dup p.(Ala1471Serfs*17) de novo mutation in the APC gene] and endoscopic investigation (multiple adenomas throughout the colon, ileum and stomach). DISCUSSION: This case report draws attention to the phenotypic spectrum of skeletal manifestations of FAP: this patient has a congenital fibula malformation, not previously associated with this syndrome, but which is likely to have been its first manifestation in this patient. This clinical case also illustrates the challenges in the early diagnosis of FAP, especially without family history, and highlights the importance of a multidisciplinary approach and the adequate study of rare skeletal abnormalities.


Assuntos
Polipose Adenomatosa do Colo , Osteoma , Masculino , Humanos , Adolescente , Proteína da Polipose Adenomatosa do Colo/genética , Fíbula/diagnóstico por imagem , Fíbula/patologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/diagnóstico , Genes APC , Mutação em Linhagem Germinativa , Osteoma/genética
2.
Gene ; 896: 148051, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38043837

RESUMO

Gardner syndrome (GS) is a specific form of familial adenomatous polyposis (FAP), which manifests as colorectal polyps, multiple osteomas and soft tissue tumors, and in the oral cavity as osteomas of the jaws, odontomas, and abnormal tooth counts. The underlying cause of GS is attributed to mutations in the APC gene. Mutations in this gene disrupt the normal functioning of the protein and lead to the development of GS. To further investigate GS, a family affected by the syndrome was selected from Dongguan, Guangdong Province. The family members underwent a comprehensive survey, which involved collecting clinical data and peripheral venous blood samples. The samples were then used for genetic analysis. Whole exome sequencing (WES) and Sanger sequencing techniques were utilized to screen and identify specific mutation sites in the APC gene. The clinical findings for the GS family included the presence of gastrointestinal polyps and odontomas. After analyzing the genetic sequencing results, a novel mutation site c.4266dupA on the APC gene was found in the patients, which leading to the APC protein truncation. As a result of this study, it is suggested that odontoma may be an early indicator of GS. Additionally, the identification of this novel mutation site in the APC gene expands the known spectrum of genetic mutations associated with the disease. This discovery has significant implications for the early diagnosis of GS, thus enabling timely intervention to reduce the risk of developing colon cancer and other related diseases.


Assuntos
Polipose Adenomatosa do Colo , Síndrome de Gardner , Odontoma , Osteoma , Humanos , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/genética , China , Síndrome de Gardner/genética , Síndrome de Gardner/complicações , Síndrome de Gardner/patologia , Genes APC , Mutação em Linhagem Germinativa , Mutação , Odontoma/complicações , Odontoma/genética , Osteoma/complicações , Osteoma/genética
3.
Int J Clin Oncol ; 28(12): 1641-1650, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37853284

RESUMO

BACKGROUND: Colorectal polyp burden is crucial for the management of patients with familial adenomatous polyposis (FAP). However, accurate evaluation of polyp burden is difficult to standardize. This study aimed to examine the possible utility of genotype-oriented management of colorectal neoplasms in patients with FAP. METHODS: Clinicopathological data from genetically proven patients with FAP was analyzed using the database of a nationwide retrospective Japanese multicenter study. The cumulative incidence of CRC was evaluated between different genotype groups. Genotype-1 were defined as germline variants on attenuated FAP-associated regions (codons 1-177, alternative splice site of exon 10 (codon 312), 1581-2843) and Genotype-2 as the other variants. Weibull and Joinpoint analyses were performed to determine the annual percentage changes in CRC risk. RESULTS: Overall, 69 men and 102 women were included. Forty-eight patients underwent colorectal resection for the first CRC, and five patients underwent resection for first cancer in the remnant anorectal segment after prophylactic surgery. The 70-year cumulative incidence of CRC in all patients was 59.3%. Patients with Genotype-1 (n = 23) demonstrated a lower risk of CRC stages II-IV than those with Genotype-2 (n = 148, P = 0.04). The risk of stage II-IV CRC was estimated to increase markedly at the age of 49 years in the Genotype-1 patients and 34 years in the Genotype-2 patients, respectively. CONCLUSIONS: Different interventional strategies based on genotypes may be proposed for the clinical management of patients with FAP. This policy needs to be validated in further prospective studies focusing on long-term endoscopic intervention and optimal age at prophylactic (procto)colectomy.


Assuntos
Polipose Adenomatosa do Colo , Genes APC , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Genótipo , Estudos Prospectivos , Estudos Retrospectivos , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/cirurgia , Polipose Adenomatosa do Colo/patologia
4.
Cancer Sci ; 114(12): 4596-4606, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37798255

RESUMO

Familial adenomatous polyposis (FAP) patients develop various life-threatening extracolonic comorbidities that appear individually or within a family. This diversity can be explained by the localization of the adenomatous polyposis coli (APC) variant, but few reports provide definitive findings about genotype-phenotype correlations. Therefore, we investigated FAP patients and the association between the severe phenotypes and APC variants. Of 247 FAP patients, 126 patients from 85 families identified to have APC germline variant sites were extracted. These sites were divided into six groups (Regions A to F), and the frequency of severe comorbidities was compared among the patient phenotypes. Of the 126 patients, the proportions of patients with desmoid tumor stage ≥III, number of FGPs ≥1000, multiple gastric neoplasms, gastric neoplasm with high-grade dysplasia, and Spigelman stage ≥III were 3%, 16%, 21%, 12%, and 41%, respectively, while the corresponding rates were 30%, 50%, 70%, 50%, and 80% in patients with Region E (codons 1398-1580) variants. These latter rates were significantly higher than those for patients with variants in other regions. Moreover, the proportion of patients with all three indicators (desmoid tumor stage ≥III, number of FGPs ≥1000, and Spigelman stage ≥III) was 20% for those with variants in Region E and 0% for those with variants in other regions. Variants in Region E indicate aggressive phenotypes, and more intensive management is required.


Assuntos
Polipose Adenomatosa do Colo , Fibromatose Agressiva , Neoplasias Gástricas , Humanos , Genes APC , Fibromatose Agressiva/genética , Genótipo , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Fenótipo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Estudos de Associação Genética , Mutação
5.
PLoS One ; 18(10): e0292643, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37824459

RESUMO

Among the small intestinal tumors that occur in irradiated mice of the established mouse model B6/B6-Chr18MSM-F1 ApcMin/+, loss of heterozygosity analysis can be utilized to estimate whether a deletion in the wild-type allele containing the Adenomatous polyposis coli (Apc) region (hereafter referred to as Deletion), a duplication in the mutant allele with a nonsense mutation at codon 850 of Apc (Duplication), or no aberration (Unidentified) has occurred. Previous research has revealed that the number of Unidentified tumors tends to increase with the radiation dose. In the present study, we investigated the molecular mechanisms underlying the development of an Unidentified tumor type in response to radiation exposure. The mRNA expression levels of Apc were significantly lower in Unidentified tumors than in normal tissues. We focused on epigenetic suppression as the mechanism underlying this decreased expression; however, hypermethylation of the Apc promoter region was not observed. To investigate whether deletions occur that cannot be captured by loss of heterozygosity analysis, we analyzed chromosome 18 using a customized array comparative genomic hybridization approach designed to detect copy-number changes in chromosome 18. However, the copy number of the Apc region was not altered in Unidentified tumors. Finally, gene mutation analysis of the Apc region using next-generation sequencing suggested the existence of a small deletion (approximately 3.5 kbp) in an Unidentified tumor from a mouse in the irradiated group. Furthermore, nonsense and frameshift mutations in Apc were found in approximately 30% of the Unidentified tumors analyzed. These results suggest that radiation-induced Unidentified tumors arise mainly due to decreased Apc expression of an unknown regulatory mechanism that does not depend on promoter hypermethylation, and that some tumors may result from nonsense mutations which are as-yet undefined point mutations.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Intestinais , Neoplasias Induzidas por Radiação , Camundongos , Animais , Genes APC , Hibridização Genômica Comparativa , Mutação , Polipose Adenomatosa do Colo/genética , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , Neoplasias Induzidas por Radiação/genética , Genômica
6.
Am J Surg Pathol ; 47(12): 1432-1437, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37811860

RESUMO

Sertoli cell tumor is a type of testicular sex cord-stromal tumor (TSCST) typically driven by gain-of-function CTNNB1 variants. Recently, molecular studies have identified TSCSTs (including Sertoli cell tumors) with loss-of-function APC variants, raising the possibility that germline APC alterations may predispose to TSCSTs. In this study, we evaluated 4 TSCSTs from 4 individual patients, including 3 APC -mutant neoplasms identified in prior studies (1 in a patient with familial adenomatous polyposis [FAP] and 2 in patients with unknown syndromic status) and 1 tumor of unknown mutational status diagnosed in a patient with known FAP. Three neoplasms were typical Sertoli cell tumors, and 1 was a malignant unclassified TSCT. All neoplasms exhibited diffuse nuclear beta-catenin expression. Non-neoplastic tissue could be obtained for DNA sequencing in the 3 Sertoli cell tumors. Comparative assessment of non-neoplastic and lesional tissue in these cases suggested that germline APC variants with subsequent inactivation of the gene (loss of heterozygosity) were the likely oncogenic driver of these Sertoli cell tumors. In the malignant unclassified TSCSTs, APC inactivation was also interpreted as the most likely driver event, and the germline origin of the variant was inferred using a recently published method. The results of this study suggest that pathogenic germline APC alterations (eg, FAP and variants thereof) may predispose to TSCSTs.


Assuntos
Polipose Adenomatosa do Colo , Tumor de Células de Sertoli , Tumores do Estroma Gonadal e dos Cordões Sexuais , Neoplasias Testiculares , Humanos , Masculino , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , beta Catenina/genética , Genes APC , Mutação em Linhagem Germinativa , Mutação , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Neoplasias Testiculares/genética
7.
Dig Dis Sci ; 68(11): 4117-4122, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37713035

RESUMO

Familial adenomatous polyposis is an autosomal dominant disease due to a mutation in the adenomatous polyposis coli (APC) gene. The disease, characterized by the development of adenomas throughout the colon and rectum, is also associated with extracolonic manifestations including gastric fundic polyps and cancer. In this report, we describe two patients with FAP with advanced gastric adenocarcinoma who received systemic chemotherapy. We reviewed the literature published over the past two decades on gastric cancer in FAP patients to assess the clinical course of this disease. Due to its recent increased incidence in Western countries, close endoscopic surveillance to detect early gastric neoplastic lesions is recommended.


Assuntos
Polipose Adenomatosa do Colo , Pólipos , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/diagnóstico , Genes APC
8.
Front Immunol ; 14: 1163466, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37533857

RESUMO

Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the Adenomatous polyposis coli (APC) gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. APC is therefore considered a tumor suppressor gene. While the role of APC in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. Our recent work indicates that the APC protein is involved in various phases of both CD4 and CD8 T cells responses. This prompted us to investigate an array of immune cell features in FAP subjects carrying APC mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. We characterized the immune cell repertoire in peripheral blood and the capacity of immune cells to respond ex vivo to different stimuli either in whole blood or in purified T cells. A variety of experimental approaches were used, including, pultiparamater flow cytometry, NanosString gene expression profiling, Multiplex and regular ELISA, confocal microscopy and computer-based image analyis methods. We found that the percentage of several T and natural killer (NK) cell populations, the expression of several genes induced upon innate or adaptive immune stimulation and the production of several cytokines and chemokines was different. Moreover, the capacity of T cells to migrate in response to chemokine was consistently altered. Finally, immunological synapses between FAP cytotoxic T cells and tumor target cells were more poorly structured. Our findings of this pilot study suggest that mild but multiple immune cell dysfunctions, together with intestinal epithelial dysplasia in FAP subjects, may facilitate the long-term polyposis and colorectal tumor development. Although at an initial discovery phase due to the limited sample size of this rare disease cohort, our findings open new perspectives to consider immune cell abnormalities into polyposis pathology.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais , Linfócitos T , Humanos , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Movimento Celular/genética , Neoplasias Colorretais/genética , Genes APC , Mutação , Projetos Piloto , Linfócitos T/imunologia
9.
Genet Med ; 25(12): 100949, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37542411

RESUMO

PURPOSE: Genomic screening can improve clinical outcomes, but presentation of individuals with risk for polyposis identified via genomic screening is unknown. To inform assessment of clinical utility of genomic screening for polyposis risk, clinical presentation of individuals in an unselected health care system cohort with an APC pathogenic or likely pathogenic (P/LP) variant causative of familial adenomatous polyposis are described. METHODS: Electronic health records of individuals with an APC P/LP variant identified via the MyCode program (MyCode APC+) were reviewed to assess adenoma burden and compare it among individuals with a clinical diagnosis of familial adenomatous polyposis and matched variant-negative controls. RESULTS: The prevalence of APC P/LP variants in this health care cohort is estimated to be 1 in 2800. Twenty-four MyCode APC+ individuals were identified during the study period. Median age at result disclosure was 53 years. Rate of clinical polyposis was 8%. Two of six participants with a classic region variant and none of those with an attenuated region variant had polyposis. MyCode APC+ participants did not differ from controls in cumulative adenoma count. CONCLUSION: APC P/LP variant prevalence estimate in the MyCode cohort is higher than prior published prevalence rates. Individuals with APC P/LP variants identified via genomic screening had a low adenoma burden.


Assuntos
Adenoma , Polipose Adenomatosa do Colo , Neoplasias Colorretais , Humanos , Pessoa de Meia-Idade , Adenoma/diagnóstico , Adenoma/epidemiologia , Adenoma/genética , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , Genes APC
10.
Genes (Basel) ; 14(7)2023 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-37510409

RESUMO

The 5q deletion syndrome is a relatively rare condition caused by the monoallelic interstitial deletion of the long arm of chromosome 5. Patients described in literature usually present variable dysmorphic features, behavioral disturbance, and intellectual disability (ID); moreover, the involvement of the APC gene (5q22.2) in the deletion predisposes them to tumoral syndromes (Familial Adenomatous Polyposis and Gardner syndrome). Although the development of gastrointestinal tract malignancies has been extensively described, the genetic causes underlying neurologic manifestations have never been investigated. In this study, we described a new patient with a 19.85 Mb interstitial deletion identified by array-CGH and compared the deletions and the phenotypes reported in other patients already described in the literature and the Decipher database. Overlapping deletions allowed us to highlight a common region in 5q22.1q23.1, identifying KCNN2 (5q22.3) as the most likely candidate gene contributing to the neurologic phenotype.


Assuntos
Proteína da Polipose Adenomatosa do Colo , Deleção Cromossômica , Genes APC , Deficiência Intelectual , Humanos , Aberrações Cromossômicas , Deficiência Intelectual/genética , Fenótipo , Proteína da Polipose Adenomatosa do Colo/genética
11.
Mol Genet Genomics ; 298(5): 1087-1105, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37289229

RESUMO

Speckle-Type Poz Protein (SPOP) involved in the regulation of proteasome-mediated degradation of several oncoproteins, resulting in cancer initiation and progression. Mutations in Adenomatous Polyposis Coli (APC) gene is reported in most sporadic and hereditary colorectal cancer (CRC). Identifying the cellular changes involved in carcinogenesis when APC is mutated is an important issue that needs attention. The tumor suppressive function of SPOP and APC has long been a major focus in the research field of colorectal cancer. However, the clinical significance of SPOP and APC gene alteration in CRC has not been established to date. Mutational analysis was performed by single-strand conformational polymorphism followed by Sanger sequencing, methylation status by methylation-specific PCR, and protein expression by immunohistochemistry on 142 tumor tissues along with their adjacent non-cancerous specimens. The overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier Curve. Mutation rates of APC and SPOP gene were 2.8% and 11.9% while that of promoter hypermethylation were 37% and 47%, respectively. The grade of differentiation and Lymph node metastasis were significantly correlated with APC methylation pattern (p ≤ 0.05). The down regulation of APC was more often seen in colonic cancer compared to rectal cancer (p = 0.07) and more commonly in T3-4 depth of invasion (p = 0.07) and in patients without lymphovascular and perineural invasion (p = 0.007, p = 0.08 respectively). The median overall survival and recurrence free survival (RFS) was 67 & 36 months while 3-yr and 5-yr OS and RFS were 61.1% & 56.4% and 49.2% & 44.8%, respectively. APC promoter methylation had a better overall survival (p = 0.035) while loss of SPOP expression had a worse survival (p = 0.09). Our findings reveal high percentage of SPOP gene mutations in CRC. A significant link is found between promoter hyper methylation and protein expression in all mutant cases of APC and SPOP, suggesting that both genes may be associated in the development of colorectal cancer in people of Indian decent. Hypermethylation of APC gene and loss of SPOP expression have shown an association with disease prognosis and could be further studied looking at its potential role in planning adjuvant treatment in CRC patients.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais , Humanos , Genes APC , Relevância Clínica , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Polipose Adenomatosa do Colo/genética , Fatores de Transcrição/genética , Metilação de DNA/genética
12.
J Comp Pathol ; 203: 26-30, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37236009

RESUMO

Cancers of the breast, prostate and intestinal tract account for most cancer-associated deaths in humans and represent several of the highest incidence human neoplasms. Therefore, understanding the underlying pathophysiology, including the formation and propagation of these cancers, is key to designing potential treatments. Over the last 50 years or more, genetically engineered mouse models (GEMMs) have been instrumental platforms to our discovery of neoplastic disease as many follow near-identical molecular and histological progression as human tumours. In this mini review, we summarize three key preclinical models and focus on some of the major findings in relation to clinical care. We discuss the MMTV-PyMT (polyomavirus middle T antigen) mouse, TRAMP (transgenic adenocarcinoma mouse prostate) mouse and APCMin (multiple intestinal neoplasm mutation of APC gene) mouse, which mimic breast, prostate and intestinal cancers, respectively. We aim to describe the significant contributions these GEMMs have made to our collective understanding of high-incidence cancers as well as briefly discuss the limitations of each model as a device for therapeutic discovery.


Assuntos
Neoplasias da Próstata , Masculino , Camundongos , Humanos , Animais , Camundongos Transgênicos , Modelos Animais de Doenças , Neoplasias da Próstata/veterinária , Genes APC , Mutação
13.
J Med Genet ; 60(11): 1035-1043, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37076288

RESUMO

While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the APC I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the APC I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais , Humanos , Predisposição Genética para Doença , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Genes APC , Fatores de Risco , Judeus/genética
14.
Int J Mol Sci ; 24(6)2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36982759

RESUMO

Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.


Assuntos
Adenoma , Polipose Adenomatosa do Colo , Neoplasias Colorretais , Humanos , Proteína da Polipose Adenomatosa do Colo/genética , Qualidade de Vida , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Colorretais/genética , Genes APC , Adenoma/genética , Carcinogênese/genética , Microambiente Tumoral
15.
Dig Dis Sci ; 68(7): 2799-2810, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36862359

RESUMO

The most prevalent type of intestinal polyposis, colorectal adenomatous polyposis (CAP), is regarded as a precancerous lesion of colorectal cancer with obvious genetic characteristics. Early screening and intervention can significantly improve patients' survival and prognosis. The adenomatous polyposis coli (APC) mutation is believed to be the primary cause of CAP. There is, however, a subset of CAP with undetectable pathogenic mutations in APC, known as APC (-)/CAP. The genetic predisposition to APC (-)/CAP has largely been associated with germline mutations in some susceptible genes, including the human mutY homologue (MUTYH) gene and the Nth-like DNA glycosylase 1 (NTHL1) gene, and DNA mismatch repair (MMR) can cause autosomal recessive APC (-)/CAP. Furthermore, autosomal dominant APC (-)/CAP could occur as a result of DNA polymerase epsilon (POLE)/DNA polymerase delta 1 (POLD1), axis inhibition protein 2 (AXIN2), and dual oxidase 2 (DUOX2) mutations. The clinical phenotypes of these pathogenic mutations vary greatly depending on their genetic characteristics. Therefore, in this study, we present a comprehensive review of the association between autosomal recessive and dominant APC (-)/CAP genotypes and clinical phenotypes and conclude that APC (-)/CAP is a disease caused by multiple genes with different phenotypes and interaction exists in the pathogenic genes.


Assuntos
Polipose Adenomatosa do Colo , Humanos , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Mutação , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Mutação em Linhagem Germinativa , Fenótipo , Genes APC
16.
Int J Mol Sci ; 24(5)2023 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-36901686

RESUMO

The activation of Wnt/ß-catenin signalling is a prerequisite for odontogenesis. APC, a member of the AXIN-CK1-GSK3ß-APC ß-catenin destruction complex, functions to modulate Wnt/ß-catenin signalling to establish regular teeth number and positions. APC loss-of-function mutations are associated with the over-activation of WNT/ß-catenin signalling and subsequent familial adenomatous polyposis (FAP; MIM 175100) with or without multiple supernumerary teeth. The ablation of Apc function in mice also results in the constitutive activation of ß-catenin in embryonic mouse epithelium and causes supernumerary tooth formation. The objective of this study was to investigate if genetic variants in the APC gene were associated with supernumerary tooth phenotypes. We clinically, radiographically, and molecularly investigated 120 Thai patients with mesiodentes or isolated supernumerary teeth. Whole exome and Sanger sequencing identified three extremely rare heterozygous variants (c.3374T>C, p.Val1125Ala; c.6127A>G, p.Ile2043Val; and c.8383G>A, p.Ala2795Thr) in APC in four patients with mesiodentes or a supernumerary premolar. An additional patient with mesiodens was compound as heterozygous for two APC variants (c.2740T>G, p.Cys914Gly, and c.5722A>T, p.Asn1908Tyr). Rare variants in APC in our patients are likely to contribute to isolated supernumerary dental phenotypes including isolated mesiodens and an isolated supernumerary tooth.


Assuntos
Polipose Adenomatosa do Colo , Dente Supranumerário , Animais , Humanos , Camundongos , Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/genética , beta Catenina/genética , Genes APC , Dente Supranumerário/complicações , Dente Supranumerário/genética
17.
J Mol Med (Berl) ; 101(4): 375-385, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36808265

RESUMO

Familial adenomatous polyposis (FAP) is a precancerous, colorectal disease characterized by hundreds to thousands of adenomatous polyps caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Approximately 30% of these mutations are premature termination codons (PTC), resulting in the production of a truncated, dysfunctional APC protein. Consequently, the ß-catenin degradation complex fails to form in the cytoplasm, leading to elevated nuclear levels of ß-catenin and unregulated ß-catenin/wnt-pathway signaling. We present in vitro and in vivo data demonstrating that the novel macrolide, ZKN-0013, promotes read through of premature stop codons, leading to functional restoration of full-length APC protein. Human colorectal carcinoma SW403 and SW1417 cells harboring PTC mutations in the APC gene showed reduced levels of nuclear ß-catenin and c-myc upon treatment with ZKN-0013, indicating that the macrolide-mediated read through of premature stop codons produced bioactive APC protein and inhibited the ß-catenin/wnt-pathway. In a mouse model of adenomatous polyposis coli, treatment of APCmin mice with ZKN-0013 caused a significant decrease in intestinal polyps, adenomas, and associated anemia, resulting in increased survival. Immunohistochemistry revealed decreased nuclear ß-catenin staining in the epithelial cells of the polyps in ZKN-0013-treated APCmin mice, confirming the impact on the ß-catenin/wnt-pathway. These results indicate that ZKN-0013 may have therapeutic potential for the treatment of FAP caused by nonsense mutations in the APC gene. KEY MESSAGES: • ZKN-0013 inhibited the growth of human colon carcinoma cells with APC nonsense mutations. • ZKN-0013 promoted read through of premature stop codons in the APC gene. • In APCmin mice, ZKN-0013 treatment reduced intestinal polyps and their progression to adenomas. • ZKN-0013 treatment in APCmin mice resulted in reduced anemia and increased survival.


Assuntos
Adenoma , Polipose Adenomatosa do Colo , Humanos , Animais , Camundongos , Genes APC , beta Catenina/metabolismo , Códon sem Sentido , Polipose Adenomatosa do Colo/tratamento farmacológico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Adenoma/genética , Macrolídeos , Pólipos Intestinais/genética
18.
Eur J Hum Genet ; 31(7): 841-845, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36828923

RESUMO

Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that occurs as a result of germline mutations in the APC gene. Despite a clear clinical diagnosis of FAP, a certain proportion of the APC variants are not readily detectable through conventional genotyping routines. We accomplished genome sequencing in duo of the disease-affected proband and non-affected sibling followed by in silico predictions and a series of RNA-based assays clarifying variant functionality. By prioritizing variants obtained by genome sequencing, we discovered the novel deep intronic alteration APC:c.531 + 1482 A > G that was demonstrated to cause out-of-frame exonization of 56 base pairs from intron 5 of the gene. Further cDNA assays confirmed, that the aberrant splicing event was complete and its splice product was subject to nonsense-mediated decay. Co-segregation was observed between the variant carrier status and the disease phenotype. Cumulative evidence confirmed that APC:c.531 + 1482 A > G is a pathogenic variant causative of the disease.


Assuntos
Proteína da Polipose Adenomatosa do Colo , Polipose Adenomatosa do Colo , Humanos , Proteína da Polipose Adenomatosa do Colo/genética , Íntrons , Polipose Adenomatosa do Colo/genética , Genes APC , Sequência de Bases , Mutação em Linhagem Germinativa
19.
BMC Biol ; 21(1): 6, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36627630

RESUMO

BACKGROUND: Methods for the long-term in situ transduction of the unperturbed murine intestinal epithelium have not been developed in past research. Such a method could speed up functional studies and screens to identify genetic factors influencing intestinal epithelium biology. Here, we developed an efficient method achieving this long-sought goal. RESULTS: We used ultrasound-guided microinjections to transduce the embryonic endoderm at day 8 (E8.0) in utero. The injection procedure can be completed in 20 min and had a 100% survival rate. By injecting a small volume (0.1-0.2 µl) of concentrated virus, single shRNA constructs as well as lentiviral libraries can successfully be transduced. The new method stably and reproducibly targets adult intestinal epithelium, as well as other endoderm-derived organs such as the lungs, pancreas, liver, stomach, and bladder. Postnatal analysis of young adult mice indicates that single transduced cells at E8.0 gave rise to crypt fields that were comprised of 20-30 neighbouring crypts per crypt-field at 90 days after birth. Lentiviral targeting of ApcMin/+ mutant and wildtype mice revealed that heterozygous loss of Apc function suppresses the developmental normal growth pattern of intestinal crypt fields. This suppression of crypt field sizes did not involve a reduction of the crypt number per field, indicating that heterozygous Apc loss impaired the growth of individual crypts within the fields. Lentiviral-mediated shRNA knockdown of p53 led to an approximately 20% increase of individual crypts per field in both Apc+/+ and ApcMin/+ mice, associating with an increase in crypt size in ApcMin/+ mice but a slight reduction in crypt size in Apc+/+ mice. Overall, p53 knockdown rescued the reduction in crypt field size in Apc-mutant mice but had no effect on crypt field size in wildtype mice. CONCLUSIONS: This study develops a novel technique enabling robust and reproducible in vivo targeting of intestinal stem cells in situ in the unperturbed intestinal epithelium across different regions of the intestine. In vivo somatic gene editing and genetic screening of lentiviral libraries has the potential to speed up discoveries and mechanistic understanding of genetic pathways controlling the biology of the intestinal epithelium during development and postnatal life. The here developed method enables such approaches.


Assuntos
Genes APC , Proteína Supressora de Tumor p53 , Camundongos , Animais , Camundongos Transgênicos , Proteína Supressora de Tumor p53/metabolismo , Mucosa Intestinal/metabolismo , Células-Tronco/metabolismo
20.
J Gastrointest Cancer ; 54(1): 62-66, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35000070

RESUMO

PURPOSE: Colorectal cancer (CRC) is the third most common cancer in the world, with enhancing morbidity and mortality each year. Due to the drug resistance against CRC, the use of novel compounds besides chemotherapy is required. Natural seafood contains large amounts of biologically active substances with new chemical structures and new medicinal activities. The aim of this study was to evaluate the effects of hydroalcoholic extract of Sargassum oligocystom algae on SW742, HT-29, WiDr, and CT-26 CRC cell lines, and to evaluate the expression of P53 and APC genes using quantitative real-time PCR (RT-qPCR). METHODS: The cytotoxicity of S. oligocystom hydroalcoholic extract was determined by MTT and trypan blue methods in six different concentrations including 0.1, 0.2, 0.5, 1, 2, and 4 mg/mL on various CRC cell lines and a control group. The expression of P53 and APC genes in exposure to 2 mg/mL of the extract was also evaluated using RT-qPCR. RESULTS: The LD50 and LD90 of S. oligocystom included 0.5-1 and > 2 mg/mL, respectively mostly affecting SW742 and CT-26 cells. In the trypan blue test, 90% viability and death of cells were observed at 0.1 and 4 mg/mL of extract, respectively. The 2 mg/mL was a safe cytotoxic concentration. A significant viability decrease was observed at concentrations ≥ 1 mg/mL (p < 0.001). Sargassum oligocystom extract at 2 mg/mL significantly increased the expression of APC ranging 1.98-2.2-fold (p < 0.001) but not P53 gene which ranged 0.5-0.68-fold (p = 0.323) after 24 h. CONCLUSION: These results indicated that the brown algae S. oligocystom extract had significant antitumor effects against the SW742, HT-29, WiDr, and CT-26 CRC cell lines and especially CT-26, suggesting that it may be a potential candidate for further studies and therefore designing drugs of natural anticancer origin. The S. oligocystom had an anticancer effect via an increase in the APC gene expression.


Assuntos
Neoplasias Colorretais , Sargassum , Humanos , Apoptose , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Genes APC , Células HT29 , Sargassum/química , Tomografia Computadorizada por Raios X , Azul Tripano/farmacologia , Azul Tripano/uso terapêutico
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