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1.
Anal Chem ; 95(28): 10812-10819, 2023 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-37402311

RESUMEN

Radioligand therapy (RLT) has gained significant momentum in recent years in the diagnosis, treatment, and monitoring of cancers. In preclinical development, the safety profile of RLT drug candidate(s) is investigated at relatively low dose levels using the cold (non-radioactive, e.g., 175Lu) ligand as a surrogate of the hot (radioactive, e.g., 177Lu) one in the "ligand-linker-chelator" complex. The formulation of the test article used in preclinical safety studies contains a mixture of free ligand (i.e., ligand-linker-chelator without metal) and cold ligand (i.e., ligand-linker-chelator with non-radioactive metal) in a similar molar ratio as seen under the manufacturing conditions for the RLT drug for clinical use, where only a fraction of free ligand molecules chelate the radioactive metal to form a hot ligand. In this very first report of LC-MS/MS bioanalysis of RLT molecules in support of a regulated preclinical safety assessment study, a highly selective and sensitive LC-MS/MS bioanalytical method was developed for the simultaneous determination of free ligand (NVS001) and cold ligand (175Lu-NVS001) in rat and dog plasma. Several unexpected technical challenges in relation to LC-MS/MS of RLT molecules were successfully addressed. The challenges include poor assay sensitivity of the free ligand NVS001, formation of the free ligand (NVS001) with endogenous metal (e.g., potassium), Ga loss from the Ga-chelated internal standard during sample extraction and analysis, "instability" of the analytes at low concentrations, and inconsistent IS response in the extracted plasma samples. The methods were validated according to the current regulatory requirements in a dynamic range of 0.5-250 ng/mL for both the free and cold ligands using a 25 µL sample volume. The validated method was successfully implemented in sample analysis in support of regulated safety studies, with very good results from incurred sample reanalysis. The current LC-MS/MS workflow can be expanded to quantitative analysis of other RLTs in support of preclinical RLT drug development.


Asunto(s)
Espectrometría de Masas en Tándem , Ratas , Animales , Perros , Cromatografía Liquida/métodos , Ligandos , Toxicocinética , Espectrometría de Masas en Tándem/métodos , Reproducibilidad de los Resultados
2.
Bioanalysis ; 15(11): 637-651, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37170582

RESUMEN

Background: Dysregulation of the kynurenine metabolic pathway has been reported in several neurological conditions. Methods & results: Sensitive and selective LC-MS/MS methods have been validated for six kynurenine pathway metabolites in human cerebrospinal fluid and plasma. For each matrix, we validated three methods - one for the simultaneous determination of kynurenine, kynurenic acid, anthranilic acid and 3-hydroxy-kynurenine (four-analyte assay), one for quinolinic acid and one for tryptophan - using stable-isotopically labeled internal standards. The dynamic range and quantitation limits were based on endogenous concentrations for each analyte. Conclusion: The use of validated methods for kynurenine pathway metabolites in human cerebrospinal fluid and plasma will provide definitive information in neurological diseases.


Asunto(s)
Quinurenina , Espectrometría de Masas en Tándem , Humanos , Cromatografía Liquida , Espectrometría de Masas en Tándem/métodos , Triptófano , Plasma/metabolismo , Ácido Quinolínico/líquido cefalorraquídeo
3.
Artículo en Inglés | MEDLINE | ID: mdl-36554301

RESUMEN

(1) Importance: Alzheimer's disease (AD) is complex and only partially understood. Analyzing the relationship between other more treatable or preventable diseases and AD may help in the prevention and the eventual development of treatments for AD. Risk estimation in a high-risk population, rather than a population already affected with AD, may reduce some bias in risk estimates. (2) Objective: To examine the rates of various comorbidities and cancers in individuals at high-risk for AD, but without a clinical diagnosis, relative to individuals from the same population with normal AD risk. (3) Design, Setting, and Participants: We conducted a study using data from the Utah Population Database (UPDB). The UPDB contains linked data from the Utah Cancer Registry, Utah death certificates, the Intermountain Health patient population, and the University of Utah Health patient population. Subjects were selected based on the availability of ancestral data, linked health information, and self-reported biometrics. (4) Results: In total, 75,877 participants who were estimated to be at high risk for AD based on family history, but who did not have an active AD diagnosis, were analyzed. A lower incidence of diabetes (RR = 0.95, 95% CI [0.92,0.97], p < 0.001), hypertension (RR = 0.97, 95% CI [0.95,0.99], p < 0.001), and heart disease (RR = 0.95, 95% CI [0.93,0.98], p < 0.001) was found. There was no difference in rates of cerebrovascular disease or other forms of dementia. Of the 15 types of cancer analyzed: breast (RR = 1.23, 95% CI [1.16, 1.30], p < 0.001); colorectal (RR = 1.30, 95% CI [1.21, 1.39], p < 0.001); kidney (RR = 1.49, 95% CI (1.29, 1.72), p < 0.001); lung (RR = 1.25, 95% CI [1.13, 1.37], p < 0.001); non-Hodgkin's Lymphoma (RR = 1.29, 95% CI [1.15, 1.44], p < 0.001); pancreas (RR = 1.34, 95% CI [1.16, 1.55], p < 0.001); stomach (RR = 1.59, 95% CI [1.36, 1.86], p < 0.001); and bladder (RR = 1.40, 95% CI [1.25, 1.56], p < 0.001), cancers were observed in significant excess among individuals at high-risk for AD after correction for multiple testing. (5) Conclusions and Relevance: Since age is the greatest risk factor for the development of AD, individuals who reach more advanced ages are at increased risk of developing AD. Consistent with this, people with fewer comorbidities earlier in life are more likely to reach an age where AD becomes a larger risk. Our findings show that individuals at high risk for AD have a decreased incidence of various other diseases. This is further supported by our finding that our high-risk group was also found to have an increased incidence of various cancers, which also increase in risk with age. There is the possibility that a more meaningful or etiological relationship exists among these various comorbidities. Further research into the etiological relationship between AD and these comorbidities may elucidate these possible interactions.


Asunto(s)
Enfermedad de Alzheimer , Neoplasias , Humanos , Enfermedad de Alzheimer/epidemiología , Neoplasias/epidemiología , Comorbilidad , Incidencia , Factores de Riesgo
4.
Neuro Oncol ; 23(2): 277-283, 2021 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-32644145

RESUMEN

BACKGROUND: There is evidence for an inherited contribution to primary brain cancer. Linkage analysis of high-risk brain cancer pedigrees has identified candidate regions of interest in which brain cancer predisposition genes are likely to reside. METHODS: Genome-wide linkage analysis was performed in a unique set of 11 informative, extended, high-risk primary brain cancer pedigrees identified in a population genealogy database, which include from 2 to 6 sampled, related primary brain cancer cases. Access to formalin-fixed paraffin embedded tissue samples archived in a biorepository allowed analysis of extended pedigrees. RESULTS: Individual high-risk pedigrees were singly informative for linkage at multiple regions. Suggestive evidence for linkage was observed on chromosomes 2, 3, 14, and 16. The chromosome 16 region in particular contains a promising candidate gene, pyridoxal-dependent decarboxylase domain-containing 1 (PDXDC1), with prior evidence for involvement with glioblastoma from other previously reported experimental settings, and contains the lead single nucleotide polymorphism (rs3198697) from the linkage analysis of the chromosome 16 region. CONCLUSIONS: Pedigrees with a statistical excess of primary brain cancers have been identified in a unique genealogy resource representing the homogeneous Utah population. Genome-wide linkage analysis of these pedigrees has identified a potential candidate predisposition gene, as well as multiple candidate regions that could harbor predisposition loci, and for which further analysis is suggested.


Asunto(s)
Neoplasias Encefálicas , Piridoxal , Neoplasias Encefálicas/genética , Predisposición Genética a la Enfermedad , Humanos , Linaje , Utah
5.
Genet Epidemiol ; 44(7): 778-784, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32677164

RESUMEN

Family history and body mass index (BMI) are well-known risk factors for colorectal cancer (CRC), however, their joint effects are not well described. Using linked data for genealogy, self-reported height and weight from driver's licenses, and the Utah Surveillance, Epidemiology, and End-Results cancer registry, we found that an increasing number of first-degree relatives (FDR) with CRC is associated with higher standardized incidence ratio (SIR) for overweight/obese probands but not for under/normal weight probands. For probands with two CRC-affected FDRs, the SIR = 1.91 (95% CI [0.52, 4.89]) for under/normal weight probands and SIR = 4.31 (95% CI [2.46, 7.00]) for overweight/obese probands. In the absence of CRC-affected FDRs, any number of CRC-affected SDRs did not significantly increase CRC risk for under/normal weight probands, but for overweight/obese probands with at least three CRC-affected SDRs the SIR = 2.68 (95% CI [1.29, 4.93]). In the absence of CRC-affected FDRs and SDRs, any number of CRC-affected third-degree relatives (TDRs) did not increase risk in under/normal weight probands, but significantly elevated risk for overweight/obese probands with at least two CRC-affected TDRs was observed; SIR = 1.32 (95% CI [1.04, 1.65]). For nonsyndromic CRC, maximum midlife BMI affects risk based on family history and should be taken into account for CRC risk communication when possible.


Asunto(s)
Índice de Masa Corporal , Neoplasias Colorrectales/epidemiología , Anamnesis , Obesidad/epidemiología , Linaje , Adulto , Anciano , Neoplasias Colorrectales/patología , Familia , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Sistema de Registros , Factores de Riesgo , Utah/epidemiología
6.
Int J Cancer ; 147(6): 1604-1611, 2020 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-32142164

RESUMEN

Similar family-based cancer and genealogy data from Norway and Utah allowed comparisons of the incidence of testicular cancer (TC), and exploration of the role of Scandinavian ancestry and family history of TC in TC risk. Our study utilizes data from the Utah Population Database and Norwegian Population Registers. All males born during 1951-2015 were followed for TC until the age of 29 years. A total of 1,974,287 and 832,836 males were born in Norway and Utah, respectively, of whom 2,686 individuals were diagnosed with TC in Norway and 531 in Utah. The incidence per year of TC in Norway (10.6) was twice that observed in Utah (5.1) for males born in the last period (1980-1984). The incidence rates of TC in Utah did not differ according to the presence or absence of Scandinavian ancestry (p = 0.669). Having a brother diagnosed with TC was a strong risk factor for TC among children born in Norway and Utah, with HR = 9.87 (95% CI 5.68-17.16) and 6.02 (95% CI 4.80-7.55), respectively; with even higher HR observed among the subset of children in Utah with Scandinavian ancestry (HR = 12.30, 95% CI 6.78-22.31). A clear difference in TC incidence among individuals born in Norway and descendants of Scandinavian people born in Utah was observed. These differences in TC rates point to the possibility of environmental influence. Family history of TC is a strong risk factor for developing TC in both populations.


Asunto(s)
Anamnesis/estadística & datos numéricos , Neoplasias Testiculares/epidemiología , Adolescente , Adulto , Anciano , Niño , Exposición a Riesgos Ambientales/efectos adversos , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Hermanos , Neoplasias Testiculares/etiología , Neoplasias Testiculares/genética , Utah/epidemiología , Adulto Joven
7.
Cancer Med ; 8(18): 7924-7930, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31670911

RESUMEN

BACKGROUND: There are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks. METHODS: Using a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for cancers of other sites were estimated in 143 Ewing sarcoma patients using a Cox proportional hazards model with matched controls; however, risks in relatives were estimated using internal cohort-specific cancer rates in first-, second-, and third-degree relatives. RESULTS: Cancers of three sites (breast, brain, complex genotype/karyotype sarcoma) were observed in excess in Ewing sarcoma patients. No Ewing sarcoma patients were identified among first-, second-, or third-degree relatives of Ewing sarcoma patients. Significantly increased risk for brain, lung/bronchus, female genital, and prostate cancer was observed in first-degree relatives. Significantly increased risks were observed in second-degree relatives for breast cancer, nonmelanoma eye cancer, malignant peripheral nerve sheath cancer, non-Hodgkin lymphoma, and translocation sarcomas. Significantly increased risks for stomach cancer, prostate cancer, and acute lymphocytic leukemia were observed in third-degree relatives. CONCLUSIONS: This analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives.


Asunto(s)
Familia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Sarcoma de Ewing/epidemiología , Humanos , Masculino , Vigilancia de la Población , Modelos de Riesgos Proporcionales , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Utah/epidemiología
8.
Neurology ; 92(15): e1745-e1753, 2019 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-30867271

RESUMEN

OBJECTIVE: The inherited component for Alzheimer disease (AD) risk has focused on close relatives; consideration of the full family history may improve accuracy and utility of risk estimates. METHODS: A population resource including a genealogy of Utah pioneers from the 1800s linked to Utah death certificates was used to estimate relative risk for AD based on specific family history constellations, including from first- to third-degree relatives. RESULTS: Any affected first-degree relatives (FDR) significantly increased risk of AD (≥1 FDRs: relative risk [RR] 1.73, 95% confidence interval [CI] [1.59-1.87]; ≥2 FDRs: RR 3.98 [3.26-4.82]; ≥3 FDRs: RR 2.48 [1.07-4.89]; ≥4 FDRs: RR 14.77 [5.42-32.15]). Affected second-degree relatives (SDR) increased risk even in the presence of affected FDRs (FDR = 1 with SDR = 2: RR 21.29 [5.80-54.52]). AD only in third-degree relatives (TDR) also increased risk (FDR = 0, SDR = 0, TDR ≥3: RR 1.43 [1.21-1.68]). Mixed evidence was observed for differences in risk based on maternal compared to paternal inheritance; higher risks for men than women with equivalent family history, and higher risk for individuals with at least one affected FDR regardless of the relative's age at death, were observed. CONCLUSIONS: This population-based estimation of RRs for AD based on family history ascertained from extended genealogy data indicates that inherited genetic factors have a broad influence, extending beyond immediate relatives. Providers should consider the full constellation of family history when counseling patients and families about their risk of AD.


Asunto(s)
Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Familia , Padre , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Madres , Sistema de Registros , Medición de Riesgo , Factores Sexuales , Utah/epidemiología
9.
Mol Cancer Ther ; 18(3): 726-729, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30587554

RESUMEN

There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line abiraterone acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line abiraterone acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on abiraterone acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line abiraterone acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; P = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line abiraterone acetate in men with mCRPC.


Asunto(s)
Acetato de Abiraterona/farmacología , Transportadores de Anión Orgánico/genética , Prednisona/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Supervivencia sin Enfermedad , Genotipo , Mutación de Línea Germinal/genética , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Polimorfismo de Nucleótido Simple/genética , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología
10.
Neurol Genet ; 4(4): e249, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30109265

RESUMEN

OBJECTIVE: To show the potential of a resource consisting of a genealogy of the US record linked to National Veterans Health Administration (VHA) patient data for investigation of the genetic contribution to health-related phenotypes, we present an analysis of familial clustering of VHA patients diagnosed with Alzheimer disease (AD). METHODS: Patients with AD were identified by the International Classification of Diseases code. The Genealogical Index of Familiality method was used to compare the average relatedness of VHA patients with AD with expected relatedness. Relative risks for AD were estimated in first- to fifth- degree relatives of patients with AD using population rates for AD. RESULTS: Evidence for significant excess relatedness and significantly elevated risks for AD in relatives was observed; multiple pedigrees with a significant excess of VHA patients with AD were identified. CONCLUSIONS: This analysis of AD shows the nascent power of the US Veterans Genealogy Resource, in early stages, to provide evidence for familial clustering of multiple phenotypes, and shows the utility of this VHA genealogic resource for future genetic studies.

11.
Eur J Hum Genet ; 26(8): 1188-1193, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29706638

RESUMEN

The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.


Asunto(s)
Cromosomas Humanos Par 11/genética , Melanoma/genética , Adulto , Estudios de Casos y Controles , Femenino , Ligamiento Genético , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Linaje
12.
J Natl Cancer Inst ; 110(12): 1380-1385, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-29659923

RESUMEN

Background: Statistically significant linkage of melanoma to chromosome 9q21 was previously reported in a Danish pedigree resource and independently confirmed in Utah high-risk pedigrees, indicating strong evidence that this region contains a melanoma predisposition gene. Methods: Whole-exome sequencing of pairs of related melanoma case subjects from two pedigrees with evidence of 9q21 linkage was performed to identify the responsible predisposition gene. Candidate variants were tested for association with melanoma in an independent set of 454 unrelated familial melanoma case subjects and 396 unrelated cancer-free control subjects from Utah, and 1534 melanoma case subjects and 1146 noncancer control subjects from Texas (MD Anderson) via a two-sided Fisher exact test. Results: A rare nonsynonymous variant in Golgi Membrane Protein 1 (GOLM1), rs149739829, shared in two hypothesized predisposition carriers in one linked pedigree was observed. Segregation of this variant in additional affected relatives of the index carriers was confirmed. A statistically significant excess of carriers of the variant was observed among Utah case subjects and control subjects (odds ratio [OR] = 9.81, 95% confidence interval [CI] = 8.35 to 11.26, P < .001) and statistically significantly confirmed in Texas case subjects and control subjects (OR = 2.45, 95% CI = 1.65 to 3.25, P = .02). Conclusion: These findings support GOLM1 as a candidate melanoma predisposition gene.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Variación Genética , Melanoma/genética , Proteínas de la Membrana/genética , Neoplasias Cutáneas/genética , Alelos , Estudios de Casos y Controles , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Melanoma/diagnóstico , Melanoma/epidemiología , Melanoma/mortalidad , Linaje , Sistema de Registros , Programa de VERF , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/mortalidad , Texas , Utah , Secuenciación del Exoma , Melanoma Cutáneo Maligno
13.
J Am Acad Dermatol ; 79(2): 238-244, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29499295

RESUMEN

BACKGROUND: Survival data are mixed comparing patients with multiple primary melanomas (MPM) to those with single primary melanomas (SPM). OBJECTIVES: We compared MPM versus SPM patient survival using a matching method that avoids potential biases associated with other analytic approaches. METHODS: Records of 14,138 individuals obtained from the Surveillance, Epidemiology, and End Results registry of all melanomas diagnosed or treated in Utah between 1973 and 2011 were reviewed. A single matched control patient was selected randomly from the SPM cohort for each MPM patient, with the restriction that they survived at least as long as the interval between the first and second diagnoses for the matched MPM patient. RESULTS: Survival curves (n = 887 for both MPM and SPM groups) without covariates showed a significant survival disadvantage for MPM patients (chi-squared 39.29, P < .001). However, a multivariate Cox proportional hazards model showed no significant survival difference (hazard ratio 1.07, P = .55). Restricting the multivariate analysis to invasive melanomas also showed no significant survival difference (hazard ratio 0.99, P = .96). LIMITATIONS: Breslow depth, ulceration status, and specific cause of death were not available for all patients. CONCLUSIONS: Patients with MPM had similar survival times as patients with SPM.


Asunto(s)
Melanoma/mortalidad , Neoplasias Primarias Múltiples/mortalidad , Neoplasias Cutáneas/mortalidad , Adulto , Anciano , Causas de Muerte , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Análisis por Apareamiento , Melanoma/patología , Persona de Mediana Edad , Neoplasias Primarias Múltiples/patología , Modelos de Riesgos Proporcionales , Programa de VERF , Neoplasias Cutáneas/patología , Úlcera Cutánea/patología , Utah/epidemiología , Melanoma Cutáneo Maligno
15.
Genome Med ; 9(1): 100, 2017 11 29.
Artículo en Inglés | MEDLINE | ID: mdl-29183403

RESUMEN

BACKGROUND: While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. METHODS: We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. RESULTS: Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aß42 (p value = 0.0003) and in the Aß42/Aß40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). CONCLUSIONS: Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.


Asunto(s)
Enfermedad de Alzheimer/genética , Proteínas de Unión al GTP rab/genética , Anciano de 80 o más Años , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Masculino , Ratones , Proteínas de Unión al GTP Monoméricas/genética , Polimorfismo de Nucleótido Simple
18.
Hum Genet ; 135(8): 923-38, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27262462

RESUMEN

Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Proteínas Supresoras de Tumor/genética , Anciano , Frecuencia de los Genes , Genotipo , Haplotipos/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/patología , Factores de Riesgo
19.
Neurology ; 87(3): 289-94, 2016 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-27170569

RESUMEN

OBJECTIVE: To estimate the risks for cancer (overall and site-specific) in an amyotrophic lateral sclerosis (ALS) cohort. METHODS: In this observational longitudinal study, ALS and cancer cases were identified in a computerized Utah genealogy database (Utah Population Database) linked to a statewide cancer registry and death certificates. Hazard ratios (HRs) were estimated as the ratio of observed to expected number of cancers. Site-specific rates for cancer were estimated within the Utah Population Database; sex, birth year (5-year range), and birth state (Utah or not) cohorts were used to estimate the expected number of cancers among ALS cases. To account for an overall shortened lifespan, Cox regression was used to include years at risk in estimation of cancer risks for ALS cases. RESULTS: An overall decreased hazard (hazard ratio [HR] 0.80, p = 0.014, 95% confidence interval [CI] 0.66-0.96) was found for cancer of any site in 1,081 deceased patients with ALS. A decreased hazard was found for lung cancer (HR 0.23, p = 0.002, CI 0.05-0.63). An increased hazard was found for salivary (HR 5.27, p = 0.041, 95% CI 1.09-15.40) and testicular (HR 3.82, p = 0.042, 95% CI 1.06-9.62) cancers. A nonsignificant hazard was observed for cutaneous malignant melanoma (HR 1.62, p = 0.12, 95% CI 0.88-2.71) for which increased risk has previously been reported. CONCLUSIONS: Using a unique population database, the overall risk of cancer of any site was found to be significantly reduced in cases with ALS, as was the risk of lung cancer. Significantly increased risk was observed for salivary and testicular cancers.


Asunto(s)
Esclerosis Amiotrófica Lateral/epidemiología , Neoplasias/epidemiología , Anciano , Comorbilidad , Bases de Datos Factuales , Femenino , Humanos , Estudios Longitudinales , Masculino , Modelos de Riesgos Proporcionales , Factores de Riesgo , Utah/epidemiología
20.
J Urol ; 196(4): 1112-6, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27150425

RESUMEN

PURPOSE: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy. MATERIALS AND METHODS: We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with abiraterone acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or more minor alleles contributes to increased risk. Subset analyses were done to determine whether metastasis site, or prior treatment with ketoconazole or docetaxel would interact with the single nucleotide polymorphisms investigated. RESULTS: Six single nucleotide polymorphisms in the estrogen sulfotransferase gene SULT1E1 were associated with time to treatment failure on abiraterone acetate therapy after false discovery rate (q value) correction for multiple testing while controlling for Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation (q <0.05). CONCLUSIONS: Single nucleotide polymorphisms in SULT1E1 were significantly associated with time to treatment failure in men on abiraterone acetate therapy. The single nucleotide polymorphisms may serve as predictive markers for treatment with abiraterone acetate.


Asunto(s)
Acetato de Abiraterona/administración & dosificación , ADN de Neoplasias/genética , Polimorfismo Genético , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Sulfotransferasas/genética , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Supervivencia sin Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Orquiectomía , Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/secundario , Estudios Retrospectivos , Sulfotransferasas/metabolismo , Resultado del Tratamiento
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