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2.
Epigenetics ; : 1-18, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33356812

RESUMO

Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3'UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, -148a or -152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3'UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

3.
Cancer ; 127(1): 103-114, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33048355

RESUMO

BACKGROUND: Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed. METHODS: Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data. RESULTS: A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers. CONCLUSIONS: Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

4.
Lancet Oncol ; 21(8): e386-e397, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32758476

RESUMO

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.


Assuntos
Síndromes Neoplásicas Hereditárias , Neoplasias Gástricas , Humanos
6.
Fam Cancer ; 19(3): 223-239, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32172433

RESUMO

Multigene panel tests for hereditary cancer syndromes are increasingly utilized in the care of colorectal cancer (CRC) and polyposis patients. However, widespread availability of panels raises a number of questions including which patients should undergo testing, which genes should be included on panels, and the settings in which panels should be ordered and interpreted. To address this knowledge gap, key questions regarding the major issues encountered in clinical evaluation of hereditary CRC and polyposis were designed by the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position Statement Committee and leadership. A literature search was conducted to address these questions. Recommendations were based on the best available evidence and expert opinion. This position statement addresses which genes should be included on a multigene panel for a patient with a suspected hereditary CRC or polyposis syndrome, proposes updated genetic testing criteria, discusses testing approaches for patients with mismatch repair proficient or deficient CRC, and outlines the essential elements for ordering and disclosing multigene panel test results. We acknowledge that critical gaps in access, insurance coverage, resources, and education remain barriers to high-quality, equitable care for individuals and their families at increased risk of hereditary CRC.

11.
Gastroenterol Hepatol (N Y) ; 15(9): 462-470, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31787853

RESUMO

A number of inherited syndromes affect the gastrointestinal tract, including Lynch syndrome and other hereditary colorectal cancers, hereditary polyposis, hereditary gastric cancer, hereditary pancreatic cancer, and hereditary pancreatitis. Recognition and diagnosis of these syndromes are paramount because affected individuals and family members can be offered life-saving screening, risk-reducing surgeries, and other therapies. Genetic counseling and testing are critical components of risk assessment and diagnosis of inherited syndromes. With the advent of next-generation sequencing, multigene panels have significantly changed the practice of genetic counseling and testing. Gastroenterology providers interface with patients who are at risk for inherited gastrointestinal syndromes; thus, providers should learn to recognize these syndromes and know when to refer their patients. Additionally, gastroenterology providers should have an understanding of genetic counseling and be able to interpret multigene panel test results. This article provides an overview of and practical tips for the assessment and diagnosis of hereditary gastrointestinal cancer syndromes and pancreatitis.

12.
Curr Treat Options Gastroenterol ; 17(4): 666-680, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31677041

RESUMO

PURPOSE OF REVIEW: Identification of Lynch syndrome is important from an individual patient and public health standpoint. As paradigms for Lynch syndrome diagnosis have shifted in recent years, this review will discuss rationale and limitations for current strategies as well as provide an overview of future directions in the field. RECENT FINDINGS: In recent years, the use of clinical criteria and risk scores for identification of Lynch syndrome has been augmented by universal testing of all newly diagnosed colorectal cancers with molecular methods to screen for mismatch repair deficiency with high sensitivity and specificity. Studies of implementation and outcomes of universal testing in clinical practice have demonstrated significant heterogeneity that results in suboptimal uptake and contributes to disparities in diagnosis. Emerging technologies, such as next-generation sequencing, hold significant promise as a screening strategy for Lynch syndrome. Universal testing for Lynch syndrome is being performed with increasing frequency, although real-world outcomes have demonstrated room for improvement. Future directions in Lynch syndrome diagnosis will involve optimization of universal testing workflow and application of new genetics technologies.

13.
Am J Gastroenterol ; 114(10): 1587-1592, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31274511

RESUMO

Celiac disease is a common inflammatory disease triggered by dietary gluten in genetically susceptible individuals. The strongest and best-characterized genetic susceptibilities in celiac disease are class II human leukocyte antigen (HLA) genes known as HLA-DQ2 and DQ8. HLA genetic testing is available through a number of commercial and academic laboratories and is used in the evaluation of celiac disease and to identify at-risk family members. Importantly, HLA genetic testing has a high negative predictive value for celiac disease, but a low positive predictive value. Therefore, for a practicing clinician, it is important to understand when to order HLA genetic testing, what test to order, and how to interpret the result. This review provides a practical primer on HLA genetics in celiac disease.


Assuntos
Doença Celíaca/diagnóstico , Testes Genéticos/normas , Antígenos HLA-DQ/genética , Guias de Prática Clínica como Assunto , Biomarcadores/sangue , Biópsia , Doença Celíaca/sangue , Doença Celíaca/genética , Doença Celíaca/imunologia , Duodeno/imunologia , Duodeno/metabolismo , Duodeno/patologia , Gastroenterologia/normas , Predisposição Genética para Doença , Glutens/imunologia , Glutens/metabolismo , Antígenos HLA-DQ/imunologia , Humanos , Absorção Intestinal/genética , Absorção Intestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Valor Preditivo dos Testes
14.
Artigo em Inglês | MEDLINE | ID: mdl-31351134

RESUMO

The incidence of colorectal cancer (CRC) and cancer-related mortality has increased in patients <55 years old.1 Consensus on optimal intervals for post-CRC surveillance colonoscopy in young patients is lacking. The primary endpoint of this study was comparison of rates of metachronous advanced neoplasia (AN) in patients diagnosed with CRC at <50 and 50-75 years. The secondary aim was to evaluate risk factors of metachronous AN.

15.
Fam Cancer ; 18(3): 331-342, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30989425

RESUMO

Many colorectal cancers (CRCs) that exhibit microsatellite instability (MSI) are not explained by MLH1 promoter methylation or germline mutations in mismatch repair (MMR) genes, which cause Lynch syndrome (LS). Instead, these Lynch-like syndrome (LLS) patients have somatic mutations in MMR genes. However, many of these patients are young and have relatives with cancer, suggesting a hereditary entity. We performed germline sequence analysis in LLS patients and determined their tumor's mutational profiles using FFPE DNA. Six hundred and fifty-four consecutive CRC patients were screened for suspected LS using MSI and absence of MLH1 methylation. Suspected LS cases were exome sequenced to identify germline and somatic mutations. Single nucleotide variants were used to characterize mutational signatures. We identified 23 suspected LS cases. Germline sequence analysis of 16 available samples identified five cases with LS mutations and 11 cases without LS mutations, LLS. Most LLS tumors had a combination of somatic MMR gene mutation and loss of heterozygosity. LLS patients were relatively young and had excess first-degree relatives with cancer. Four of the 11 LLS patients had rare likely pathogenic variants in genes that maintain genome integrity. Moreover, tumors from this group had a distinct mutational signature compared to tumors from LLS patients lacking germline mutations in these genes. In summary, more than a third of the LLS patients studied had germline mutations in genes that maintain genome integrity and their tumors had a distinct mutational signature. The possibility of hereditary factors in LLS warrants further studies so counseling can be properly informed.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Mutação em Linhagem Germinativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Heterozigoto , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Análise de Sequência de DNA
17.
PLoS One ; 14(2): e0212509, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785946

RESUMO

INTRODUCTION: A small bowel source is suspected when evaluation of overt gastrointestinal (GI) bleeding with upper and lower endoscopy is negative. Video capsule endoscopy (VCE) is the recommended next diagnostic test for small bowel bleeding sources. However, clinical or endoscopic predictive factors for small bowel bleeding in the setting of an overt bleeding presentation are unknown. We aimed to define predictive factors for positive VCE among individuals presenting with overt bleeding and a suspected small bowel source. METHODS: We included consecutive inpatient VCE performed between September 1, 2012 to September 1, 2015 for melena or hematochezia at two tertiary centers. All patients had EGD and colonoscopy performed prior to VCE. Patient demographics, medication use, and endoscopic findings were retrospectively recorded. VCE findings were graded based on the P0-P2 grading system. The primary outcome of interest was a positive (P2) VCE. The secondary outcome of interest was the performance of a therapeutic intervention. Data were analyzed with the Fisher exact test for dichotomous variables and logistic regression. RESULTS: Two hundred forty-three VCE were reviewed, and 117 were included in the final analysis. A positive VCE (P2) was identified in 35 (29.9%) cases. In univariate analysis, a positive VCE was inversely associated with presence of diverticula on preceding colonoscopy (OR: 0.44, 95% CI: 0.2-0.99), while identification of blood on terminal ileal examination was associated with a positive VCE (OR: 5.18, 95% CI: 1.51-17.76). In multivariate analysis, only blood identified on terminal ileal examination remained a significant risk factor for positive VCE (OR: 6.13, 95% CI: 1.57-23.81). Blood on terminal ileal examination was also predictive of therapeutic intervention in both univariate (OR: 4.46, 95% CI: 1.3-15.2) and multivariate analysis (OR: 5.04, 95% CI: 1.25-20.32). CONCLUSION: Among patients presenting with overt bleeding but negative upper and lower endoscopy, the presence of blood on examination of the terminal ileum is strongly associated with a small bowel bleeding source as well as with small bowel therapeutic intervention. Presence of diverticula on colonoscopy is inversely associated with a positive VCE and therapeutic intervention in univariate analysis.


Assuntos
Endoscopia Gastrointestinal/métodos , Hemorragia Gastrointestinal/diagnóstico , Enteropatias/diagnóstico , Intestino Delgado , Idoso , Idoso de 80 Anos ou mais , Endoscopia por Cápsula , Colonoscopia , Feminino , Hemorragia Gastrointestinal/diagnóstico por imagem , Humanos , Íleo/diagnóstico por imagem , Enteropatias/diagnóstico por imagem , Intestino Delgado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco
19.
Cell ; 176(5): 967-981.e19, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30739797

RESUMO

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD. VIDEO ABSTRACT.


Assuntos
Doença Celíaca/imunologia , Inflamação/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Antígenos , Butirofilinas/metabolismo , Doença Celíaca/fisiopatologia , Doença Crônica , Dieta Livre de Glúten , Glutens/metabolismo , Células HEK293 , Humanos , Inflamação/metabolismo , Mucosa Intestinal/imunologia , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
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