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1.
BMC Cardiovasc Disord ; 21(1): 126, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33673806

RESUMEN

BACKGROUND: Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world. METHODS: A retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic. RESULTS: A total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p < 0.0001), a higher maximum wall thickness (MWT) (p < 0.0001), a positive family history (p < 0.0001), the absence of hypertension (p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004). CONCLUSION: The diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population.


Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico , Pruebas Genéticas , Variación Genética , Adolescente , Adulto , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Niño , Preescolar , Femenino , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Fenotipo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto Joven
2.
Am J Med Genet C Semin Med Genet ; 184(3): 631-643, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32770643

RESUMEN

Pathogenic variants in the gene HGSNAT (heparan-α-glucosaminide N-acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)-a severe childhood-onset lysosomal storage disorder, and adult-onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to-date of HGSNAT-associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late-onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543-2A>C; c.1708delA], three of which were considered to be retina-disease-specific alleles. The most prevalent retina-disease-specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans-acting genetic or environmental modifying factors.


Asunto(s)
Acetiltransferasas/genética , Mucopolisacaridosis III/genética , Enfermedades de la Retina/genética , Retinitis Pigmentosa/genética , Adolescente , Adulto , Niño , Femenino , Genotipo , Humanos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Mucopolisacaridosis III/complicaciones , Mucopolisacaridosis III/patología , Linaje , Retina/patología , Enfermedades de la Retina/complicaciones , Enfermedades de la Retina/patología , Retinitis Pigmentosa/complicaciones , Retinitis Pigmentosa/patología , Adulto Joven
3.
Int J Cancer ; 142(3): 540-546, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28960316

RESUMEN

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.


Asunto(s)
Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Estudios de Casos y Controles , Estudios de Cohortes , Estonia/epidemiología , Finlandia/epidemiología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , Sistema de Registros
4.
Hum Mol Genet ; 25(11): 2349-2359, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27005424

RESUMEN

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Neoplasias Colorrectales/genética , Enfermedades Inflamatorias del Intestino/genética , Proteínas de la Membrana/genética , Proteínas Musculares/genética , Pueblo Asiatico , Neoplasias Colorrectales/patología , Femenino , Pleiotropía Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Enfermedades Inflamatorias del Intestino/patología , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Población Blanca
5.
Int J Cancer ; 140(12): 2701-2708, 2017 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-28340513

RESUMEN

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.


Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad/genética , Hiperlipidemias/genética , Análisis de la Aleatorización Mendeliana/métodos , Polimorfismo de Nucleótido Simple , Colesterol/sangre , Neoplasias Colorrectales/sangre , Estudio de Asociación del Genoma Completo/métodos , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Hiperlipidemias/sangre , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Modelos Logísticos , Oportunidad Relativa , Medición de Riesgo , Factores de Riesgo , Triglicéridos/sangre
6.
Hum Mol Genet ; 24(15): 4407-16, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-25964426

RESUMEN

Uterine leiomyomas are extremely frequent benign smooth muscle tumors often presenting as multiple concurrent lesions and causing symptoms such as abnormal menstrual bleeding, abdominal pain and infertility. While most leiomyomas are believed to arise independently, a few studies have encountered separate lesions harboring identical genetic changes, suggesting a common clonal origin. To investigate the frequency of clonally related leiomyomas, genome-wide tools need to be utilized, and thus little is known about this phenomenon. Using MED12 sequencing and SNP arrays, we searched for clonally related uterine leiomyomas in a set of 103 tumors from 14 consecutive patients who entered hysterectomy owing to symptomatic lesions. Whole-genome sequencing was also utilized to study the genomic architecture of clonally related tumors. This revealed four patients to have two or more tumors that were clonally related, all of which lacked MED12 mutations. Furthermore, some tumors were composed of genetically distinct subclones, indicating a nonlinear, branched model of tumor evolution. DEPDC5 was discovered as a novel tumor suppressor gene playing a role in the progression of uterine leiomyomas. Perhaps counterintuitively­considering Knudson's two-hit hypothesis­a large shared deletion was followed by different truncating DEPDC5 mutations in four clonally related leiomyomas. This study provides insight into the intratumor heterogeneity of these tumors and suggests that a shared clonal origin is a common feature of leiomyomas that do not carry an MED12 mutation. These observations also offer one explanation to the common occurrence of multiple concurrent lesions.


Asunto(s)
Leiomioma/genética , Complejo Mediador/genética , Neoplasias/genética , Proteínas Represoras/genética , Neoplasias Uterinas/genética , Carcinogénesis/genética , Células Clonales , Femenino , Proteínas Activadoras de GTPasa , Predisposición Genética a la Enfermedad , Genoma Humano , Humanos , Leiomioma/patología , Mutación , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Neoplasias Uterinas/patología
7.
Br J Cancer ; 115(2): 266-72, 2016 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-27336604

RESUMEN

BACKGROUND: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. METHODS: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. RESULTS: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively. CONCLUSIONS: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.


Asunto(s)
Adiposidad/genética , Neoplasias Colorrectales/complicaciones , Adulto , Neoplasias Colorrectales/genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Distribución Aleatoria
8.
PLoS Genet ; 9(10): e1003876, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24146633

RESUMEN

Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.


Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad , Pérdida de Heterocigocidad/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Exoma , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Linaje
9.
Int J Cancer ; 135(3): 611-23, 2014 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-24382590

RESUMEN

ARID1A has been identified as a novel tumor suppressor gene in ovarian cancer and subsequently in various other tumor types. ARID1A belongs to the ARID domain containing gene family, which comprises of 15 genes involved, for example, in transcriptional regulation, proliferation and chromatin remodeling. In this study, we used exome sequencing data to analyze the mutation frequency of all the ARID domain containing genes in 25 microsatellite unstable (MSI) colorectal cancers (CRCs) as a first systematic effort to characterize the mutation pattern of the whole ARID gene family. Genes which fulfilled the selection criteria in this discovery set (mutations in at least 4/25 [16%] samples, including at least one nonsense or splice site mutation) were chosen for further analysis in an independent validation set of 21 MSI CRCs. We found that in addition to ARID1A, which was mutated in 39% of the tumors (18/46), also ARID1B (13%, 6/46), ARID2 (13%, 6/46) and ARID4A (20%, 9/46) were frequently mutated. In all these genes, the mutations were distributed along the entire length of the gene, thus distinguishing them from typical MSI target genes previously described. Our results indicate that in addition to ARID1A, other members of the ARID gene family may play a role in MSI CRC.


Asunto(s)
Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Exoma/genética , Repeticiones de Microsatélite/genética , Mutación/genética , Proteínas Nucleares/genética , Proteína 1 de Unión a Retinoblastoma/genética , Factores de Transcripción/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico
10.
Gastroenterology ; 145(3): 540-3.e22, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23684749

RESUMEN

Microsatellite instability can be found in approximately 15% of all colorectal cancers. To detect new oncogenes we sequenced the exomes of 25 colorectal tumors and respective healthy colon tissue. Potential mutation hot spots were confirmed in 15 genes; ADAR, DCAF12L2, GLT1D1, ITGA7, MAP1B, MRGPRX4, PSRC1, RANBP2, RPS6KL1, SNCAIP, TCEAL6, TUBB6, WBP5, VEGFB, and ZBTB2; these were validated in 86 tumors with microsatellite instability. ZBTB2, RANBP2, and PSRC1 also were found to contain hot spot mutations in the validation set. The form of ZBTB2 associated with colorectal cancer increased cell proliferation. The mutation hot spots might be used to develop personalized tumor profiling and therapy.


Asunto(s)
Adenocarcinoma/genética , Neoplasias Colorrectales/genética , Inestabilidad de Microsatélites , Oncogenes , Anciano , Estudios de Casos y Controles , Femenino , Marcadores Genéticos , Humanos , Masculino , Análisis de Secuencia de ADN
11.
Gut ; 62(6): 871-81, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22490517

RESUMEN

OBJECTIVE: Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. DESIGN: Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266) and in combination with gender, age and FH (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. RESULTS: The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2 × 10(-16)), confirmed in external validation sets (Sweden p=1.2 × 10(-6), Finland p=2 × 10(-5)). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. CONCLUSION: Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.


Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Alelos , Estudios de Casos y Controles , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etnología , Estudios de Factibilidad , Femenino , Genotipo , Humanos , Modelos Logísticos , Masculino , Medición de Riesgo , Factores de Riesgo , Escocia/epidemiología
12.
Gastroenterology ; 143(6): 1482-1491.e3, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22960657

RESUMEN

BACKGROUND & AIMS: Familial visceral myopathy (FVM) is a rare inherited form of myopathic pseudo-obstruction; little is known about the genetic factors that cause this disorder. FVM is characterized by impaired functions of enteric smooth muscle cells, resulting in abnormal intestinal motility, severe abdominal pain, malnutrition, and even death. We searched for genetic factors that might cause this disorder. METHODS: We performed whole-exome sequence analysis of blood samples from 2 individuals in a family that had 7 members diagnosed with FVM. Sanger sequencing was used to analyze additional family members and 280 individuals without this disorder (controls). Intestinal tissue samples from 4 patients and 2 controls were analyzed by immunohistochemistry. Functional studies, including immunofluorescence, cell contractility, and actomyosin structure analyses, were performed using CRL-1976 and U2OS sarcoma cell lines. RESULTS: Whole-exome sequence analysis of DNA from 2 siblings identified 83 gene variants that were shared between the siblings and considered as possible disease-causing changes. A heterozygous variant, R148S in enteric smooth muscle actin γ-2 (ACTG2), segregated with disease phenotype. Intestinal smooth muscle (muscularis propria) from individuals with FVM had reduced levels of cytoplasmic ACTG2 and abnormal accumulation of the protein into intracellular inclusions compared with controls. Sarcoma cells that expressed exogenous ACTG2(R148S) incorporated reduced amounts of this protein into actin filaments compared with cells expressing ACTG2(wt) (P < .001). ACTG2(R148S) also interfered with actin cytoskeleton organization and the contractile activities of the cells, indicating a dominant-negative effect. These findings, along with the site of the variation in the protein, indicate that ACTG2 R148S interferes with actin filament assembly. CONCLUSIONS: We identified the R148S variant in ACTG2 as a cause of FVM in one family. The altered ACTG2 protein appears to aggregate, rather than form actin filaments, in intestinal smooth muscle tissue. This defect could impair contraction of the visceral smooth muscle cells and reduce bowel motility.


Asunto(s)
Actinas/genética , Actinas/metabolismo , Mucosa Intestinal/metabolismo , Seudoobstrucción Intestinal/genética , Seudoobstrucción Intestinal/metabolismo , Músculo Liso/metabolismo , Mutación Missense/genética , Adulto , Segregación Cromosómica/genética , Exoma/genética , Femenino , Finlandia , Motilidad Gastrointestinal/fisiología , Estudio de Asociación del Genoma Completo , Heterocigoto , Humanos , Seudoobstrucción Intestinal/fisiopatología , Intestinos/fisiopatología , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiología , Músculo Liso/fisiopatología , Plexo Mientérico/anomalías , Plexo Mientérico/metabolismo , Plexo Mientérico/fisiopatología , Linaje , Fenotipo
13.
Scand J Gastroenterol ; 48(6): 672-8, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23544471

RESUMEN

OBJECTIVE: Early-onset colorectal cancer (CRC), defined here as age of onset less than 40 years, develops frequently in genetically predisposed individuals. Next-generation sequencing is an increasingly available option in the diagnostic workup of suspected hereditary susceptibility, but little is known about the practical feasibility and additional diagnostic yield of the technology in this patient group. MATERIALS AND METHODS: We analyzed 38 young CRC patients derived from a set of 1514 CRC cases. All 38 tumors had been tested in our laboratory for microsatellite instability (MSI), and Sanger sequencing had been used to screen for MLH1 and MSH2 mutations in MSI cases. Also, gastrointestinal polyposis had been diagnosed clinically and molecularly. Family histories were acquired from national registries. If inherited syndromes had not been diagnosed in routine diagnostic efforts (n = 23), normal tissue DNA was analyzed for mutations in a comprehensive set of high-penetrance genes (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, SMAD4, BMPR1A, LKB1/STK11, and PTEN) by exome sequencing. RESULTS: CRC predisposition syndromes were confirmed in 42% (16/38) of early-onset CRC patients. Hereditary nonpolyposis colorectal cancer was diagnosed in 12 (32%) patients, familial adenomatous polyposis in three (7.9%), and juvenile polyposis in one (2.6%) patient. Exome sequencing revealed one additional MLH1 mutation. Over half of the patients had advanced cancers (Dukes C or D, 61%, 23/38). The majority of nonsyndromic patients had unaffected first-degree relatives and microsatellite-stable tumors. CONCLUSIONS: Microsatellite instability positivity or gastrointestinal polyposis characterized all patients with unambiguous highly penetrant germline mutations. In our series, exome sequencing produced little added value in diagnosing the underlying predisposition conditions.


Asunto(s)
Poliposis Adenomatosa del Colon/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Exoma/genética , Predisposición Genética a la Enfermedad , Poliposis Intestinal/congénito , Síndromes Neoplásicos Hereditarios/diagnóstico , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Adaptadoras Transductoras de Señales/genética , Poliposis Adenomatosa del Colon/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Adenosina Trifosfatasas/genética , Adulto , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , ADN Glicosilasas/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Pruebas Genéticas , Humanos , Poliposis Intestinal/diagnóstico , Poliposis Intestinal/genética , Masculino , Inestabilidad de Microsatélites , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/genética , Síndromes Neoplásicos Hereditarios/genética , Proteínas Nucleares/genética , Fosfohidrolasa PTEN/genética , Proteínas Serina-Treonina Quinasas/genética , Análisis de Secuencia de ADN , Proteína Smad4/genética , Adulto Joven
14.
PLoS Genet ; 6(9): e1001126, 2010 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-20862326

RESUMEN

Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC.


Asunto(s)
Alelos , Cromosomas Humanos Par 8/genética , Neoplasias Colorrectales/genética , Factor 3 de Iniciación Eucariótica/genética , Predisposición Genética a la Enfermedad , Variación Genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias Colorrectales/patología , Ensayo de Cambio de Movilidad Electroforética , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros/genética , Sitios Genéticos/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Unión Proteica , Factores de Riesgo
15.
Int J Cancer ; 130(7): 1558-66, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-21544814

RESUMEN

Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in ∼ 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6-10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 6-10 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development.


Asunto(s)
Neoplasias Colorrectales/genética , ADN de Neoplasias/genética , Inestabilidad de Microsatélites , Línea Celular Tumoral , Mutación del Sistema de Lectura , Células HCT116 , Humanos , Inmunohistoquímica/métodos , Repeticiones de Microsatélite , Tasa de Mutación , Análisis de Regresión
16.
Gastroenterology ; 141(6): 2039-46, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21893118

RESUMEN

BACKGROUND & AIMS: Expression of the netrin-1 dependence receptor UNC5C is reduced in many colorectal tumors; mice with the UNC5C mutations have increased progression of intestinal tumors. We investigated whether specific variants in UNC5C increase risk of colorectal cancer (CRC). METHODS: We analyzed the sequence of UNC5C in blood samples from 1801 patients with CRC and 4152 controls from 3 cohorts (France, United States, and Finland). Almost all cases from France and the United States had familial CRC; of the Finnish cases, 92 of 984 were familial. We analyzed whether CRC segregates with the UNC5C variant A628K in 3 families with histories of CRC. We also performed haplotype analysis to determine the origin of this variant. RESULTS: Of 817 patients with familial CRC, 14 had 1 of 4 different, unreported missense variants in UNC5C. The variants p.Asp353Asn (encodes D353N), p.Arg603Cys (encodes R603C), and p.Gln630Glu (encodes Q630E) did not occur significantly more often in cases than controls. The variant p.Ala628Lys (A628K) was detected in 3 families in the French cohort (odds ratio, 8.8; Wald's 95% confidence interval, 1.47-52.93; P = .03) and in 2 families in the US cohort (odds ratio, 1.9; P = .6) but was not detected in the Finnish cohort; UNC5C A628K segregated with CRC in families. Three families with A628K had a 109-kilobase identical haplotype that spanned most of UNC5C, indicating recent origin of this variant in white subjects (14 generations; 95% confidence interval, 6-36 generations). Transfection of HEK293T cells with UNC5C-A628K significantly reduced apoptosis compared with wild-type UNC5C, measured in an assay of active caspase-3. CONCLUSIONS: Inherited mutations in UNC5C prevent apoptosis and increase risk of CRC.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Apoptosis/genética , Mutación Missense/genética , Receptores de Superficie Celular/genética , Poliposis Adenomatosa del Colon/sangre , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Haplotipos/genética , Humanos , Immunoblotting , Inmunohistoquímica , Receptores de Netrina , Linaje , Reacción en Cadena de la Polimerasa , Receptores de Superficie Celular/sangre , Factores de Riesgo
17.
Ophthalmic Genet ; 43(2): 152-158, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35240912

RESUMEN

BACKGROUND: Pathogenic variants in the CEP78 gene can present as atypical Usher syndrome or as retinitis pigmentosa. Here, we present a review of all reported cases of CEP78 variants in the literature to date and present a novel variant of CEP78, c.1261_1262delinsA, in a consanguineous northern Finnish family with two individuals. MATERIALS AND METHODS: Our patients were first discovered in a registry-based study. Later, they gave their written consent for this study. In order to describe the genotype and phenotype, their historic clinical patient data and genetic data were gathered, and a clinical ophthalmic examination and an audiogram were performed. For this review, a PubMed search using the keyword CEP78 was carried out. The first article on CEP78 was published in the year 2007, and the publications from the years 2007-2021 were included. RESULTS: A large gene panel identified a homozygous CEP78 c.1261_1262delinsA variant in two affected siblings. In addition to the classical signs of retinitis pigmentosa, both siblings had large round atrophic spots in the mid periphery, and hyperautofluorescence of the macula. Patient 1 had age-related hearing impairment; patient 2 had normal hearing. In total, 20 articles have been published about CEP78. Eight of these papers report patient data with the affected individuals typically having retinal dystrophy combined with sensorineural hearing impairment, classified as atypical Usher syndrome. CONCLUSIONS: Here, we present a comprehensive review of CEP78 and expand the knowledge of pathogenic CEP78 variants and the phenotypic variety.


Asunto(s)
Retinitis Pigmentosa , Síndromes de Usher , Proteínas de Ciclo Celular/genética , Mutación del Sistema de Lectura , Humanos , Mutación , Linaje , Fenotipo , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Síndromes de Usher/genética
18.
Transl Vis Sci Technol ; 11(1): 6, 2022 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-34985506

RESUMEN

Purpose: Comprehensive genetic testing for inherited retinal dystrophy (IRD) is challenged by difficult-to-sequence genomic regions, which are often mutational hotspots, such as RPGR ORF15. The purpose of this study was to evaluate the diagnostic contribution of RPGR variants in an unselected IRD patient cohort referred for testing in a clinical diagnostic laboratory. Methods: A total of 5201 consecutive patients were analyzed with a clinically validated next-generation sequencing (NGS)-based assay, including the difficult-to-sequence RPGR ORF15 region. Copy number variant (CNV) detection from NGS data was included. Variant interpretation was performed per the American College of Medical Genetics and Genomics guidelines. Results: A confirmed molecular diagnosis in RPGR was found in 4.5% of patients, 24.0% of whom were females. Variants in ORF15 accounted for 74% of the diagnoses; 29% of the diagnostic variants were in the most difficult-to-sequence central region of ORF15 (c.2470-3230). Truncating variants made up the majority (91%) of the diagnostic variants. CNVs explained 2% of the diagnostic cases, of which 80% were one- or two-exon deletions outside of ORF15. Conclusions: Our findings indicate that high-throughput, clinically validated NGS-based testing covering the difficult-to-sequence region of ORF15, in combination with high-resolution CNV detection, can help to maximize the diagnostic yield for patients with IRD. Translational Relevance: These results demonstrate an accurate and scalable method for the detection of RPGR-related variants, including the difficult-to-sequence ORF15 hotspot, which is relevant given current and emerging therapeutic opportunities.


Asunto(s)
Proteínas del Ojo , Distrofias Retinianas , Exones , Proteínas del Ojo/genética , Femenino , Humanos , Linaje , Prevalencia , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/epidemiología , Distrofias Retinianas/genética
19.
BMC Med Genet ; 12: 23, 2011 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-21314996

RESUMEN

BACKGROUND: Common single-nucleotide polymorphisms (SNPs) in ten chromosomal loci have been shown to predispose to colorectal cancer (CRC) in genome-wide association studies. A plausible biological mechanism of CRC susceptibility associated with genetic variation has so far only been proposed for three loci, each pointing to variants that affect gene expression through distant regulatory elements. In this study, we aimed to gain insight into the molecular basis of seven low-penetrance CRC loci tagged by rs4779584 at 15q13, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. METHODS: Possible somatic gain of the risk allele or loss of the protective allele was studied by analyzing allelic imbalance in tumour and corresponding normal tissue samples of heterozygous patients. Functional variants were searched from in silico predicted enhancer elements locating inside the CRC-associating linkage-disequilibrium regions. RESULTS: No allelic imbalance targeting the SNPs was observed at any of the seven loci. Altogether, 12 SNPs that were predicted to disrupt potential transcription factor binding sequences were genotyped in the same population-based case-control series as the seven tagging SNPs originally. None showed association with CRC. CONCLUSIONS: The results of the allelic imbalance analysis suggest that the seven CRC risk variants are not somatically selected for in the neoplastic progression. The bioinformatic approach was unable to pinpoint cancer-causing variants at any of the seven loci. While it is possible that many of the predisposition loci for CRC are involved in control of gene expression by targeting transcription factor binding sites, also other possibilities, such as regulatory RNAs, should be considered.


Asunto(s)
Desequilibrio Alélico/genética , Carcinoma/genética , Neoplasias Colorrectales/genética , Elementos de Facilitación Genéticos/genética , Sitios Genéticos , Penetrancia , Estudios de Casos y Controles , Transformación Celular Neoplásica/genética , Biología Computacional , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética
20.
Proc Natl Acad Sci U S A ; 105(14): 5513-8, 2008 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-18391202

RESUMEN

A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias Intestinales/genética , Mutación , Cadenas Pesadas de Miosina/genética , Miosina Tipo II/genética , Miosinas del Músculo Liso/genética , Poliposis Adenomatosa del Colon/genética , Secuencia de Aminoácidos , Estudios de Casos y Controles , Neoplasias Colorrectales/genética , Análisis Mutacional de ADN , Humanos , Datos de Secuencia Molecular , Síndrome de Peutz-Jeghers/genética , Miosinas del Músculo Liso/fisiología
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