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1.
Hum Genomics ; 15(1): 46, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284826

RESUMO

Increasing amounts of genetic data have led to the development of polygenic risk scores (PRSs) for a variety of diseases. These scores, built from the summary statistics of genome-wide association studies (GWASs), are able to stratify individuals based on their genetic risk of developing various common diseases and could potentially be used to optimize the use of screening and preventative treatments and improve personalized care for patients. Many challenges are yet to be overcome, including PRS validation, healthcare professional and patient education, and healthcare systems integration. Ethical challenges are also present in how this information is used and the current lack of diverse populations with PRSs available. In this review, we discuss the topics above and cover the nature of PRSs, visualization schemes, and how PRSs can be improved. With these tools on the horizon for multiple diseases, scientists, clinicians, health systems, regulatory bodies, and the public should discuss the uses, benefits, and potential risks of PRSs.


Assuntos
Doenças Genéticas Inatas/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Herança Multifatorial/genética , Humanos , Fenótipo , Fatores de Risco
2.
Cancers (Basel) ; 16(8)2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38672660

RESUMO

Breast cancer (BC) is a complex disease affecting one in eight women in the USA. Advances in population genomics have led to the development of polygenic risk scores (PRSs) with the potential to augment current risk models, but replication is often limited. We evaluated 2 robust PRSs with 313 and 3820 SNPs and the effects of multiple genotype imputation replications in BC cases and control populations. Biological samples from BC cases and cancer-free controls were drawn from three European ancestry cohorts. Genotyping on the Illumina Global Screening Array was followed by stringent quality control measures and 20 genotype imputation replications. A total of 468 unrelated cases and 4337 controls were scored, revealing significant differences in mean PRS percentiles between cases and controls (p < 0.001) for both SNP sets (313-SNP PRS: 52.81 and 48.07; 3820-SNP PRS: 55.45 and 49.81), with receiver operating characteristic curve analysis showing area under the curve values of 0.596 and 0.603 for the 313-SNP and 3820-SNP PRS, respectively. PRS fluctuations (from ~2-3% up to 9%) emerged across imputation iterations. Our study robustly reaffirms the predictive capacity of PRSs for BC by replicating their performance in an independent BC population and showcases the need to average imputed scores for reliable outcomes.

3.
Mol Oncol ; 12(10): 1753-1777, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30107089

RESUMO

Overexpression of oncoproteins is a major cause of treatment failure using current chemotherapeutic drugs. Drug-induced degradation of oncoproteins is feasible and can improve clinical outcomes in diverse types of cancers. Mortalin-2 (mot-2) is a dominant oncoprotein in several tumors, including colorectal cancer (CRC). In addition to inactivating the p53 tumor suppressor protein, mot-2 enhances tumor cell invasion and migration. Thus, mot-2 is considered a potential therapeutic target in several cancer types. The current study investigated the biological role of a ubiquitin-like protein called UBXN2A in the regulation of mot-2 turnover. An orthogonal ubiquitin transfer technology followed by immunoprecipitation, in vitro ubiquitination, and Magnetic Beads TUBE2 pull-down experiments revealed that UBXN2A promotes carboxyl terminus of the HSP70-interacting protein (CHIP)-dependent ubiquitination of mot-2. We subsequently showed that UBXN2A increases proteasomal degradation of mot-2. A subcellular compartmentalization experiment revealed that induced UBXN2A decreases the level of mot-2 and its chaperone partner, HSP60. Pharmacological upregulation of UBXN2A using a small molecule, veratridine (VTD), decreases the level of mot-2 in cancer cells. Consistent with the in vitro results, UBXN2A+/- mice exhibited selective elevation of mot-2 in colon tissues. An in vitro Anti-K48 TUBE isolation approach showed that recombinant UBXN2A enhances proteasomal degradation of mot-2 in mouse colon tissues. Finally, we observed enhanced association of CHIP with the UBXN2A-mot-2 complex in tumors in an azoxymethane/dextran sulfate sodium-induced mouse CRC model. The existence of a multiprotein complex containing UBXN2A, CHIP, and mot-2 suggests a synergistic tumor suppressor activity of UBXN2A and CHIP in mot-2-enriched tumors. This finding validates the UBXN2A-CHIP axis as a novel and potential therapeutic target in CRC.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Proteínas Mitocondriais/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Ubiquitinas/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Chaperonina 60/metabolismo , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Haploinsuficiência/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Complexos Multiproteicos/metabolismo , Fenótipo , Estabilidade Proteica , Especificidade por Substrato , Ubiquitinação
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