Predicción de riesgo de cáncer de mama en mujeres sanas de población española basado en el estudio de variantes genéticas / Prediction of cancer risk based on study of genetic variants in healthy women in the Spanish population

Objetivo: Estratificación de la población general con base en las variantes genotípicas para seleccionar a aquellas mujeres de alto riesgo a desarrollar un cáncer de mama que puedan ser candidatas a un seguimiento individualizado. Material y métodos: Se ha realizado un estudio caso-control en 856 mujeres con cáncer de mama y 839 mujeres controles de la población general pareadas por edad, analizando la asociación entre el riesgo a desarrollar cáncer de mama y un grupo de variantes basado en 76 polimorfismos de un cambio de base (SNP) de susceptibilidad. Resultados: Se han establecido 2curvas de casos y controles con base en las odds ratio (OR) genotípicas que diferencian las 2poblaciones con significación estadística (p = 2,293×10-15). Asimismo, se ha estratificado la población de casos y controles e identificado un 14% de la población que se encontraría en el grupo de alto riesgo con una OR > 2 (> 25% probabilidades de desarrollar un cáncer de mama). Este grupo sería candidato a un seguimiento individualizado. Conclusiones: El Polygenic Risk Score es un predictor del riesgo del cáncer de mama independiente que puede ayudar a seleccionar mujeres con alto riesgo para establecer medidas de seguimiento y tratamiento individualizado en función del riesgo genético

Objective: To stratify the general population based on genotypic variants in order to select women at high risk of breast cancer who could be candidates for individualized follow-up. Material and methods: We performed a case-control study in 856 women with breast cancer and 839 aged-matched control women from the general population. We analysed the association between the risk of developing breast cancer and a group of variants based on 76 susceptibility single nucleotide polymorphisms. Results: Two case-control curves were established based on genotypic odds ratios (OR) that differentiated the 2populations with statistical significance (P=2.293×10-15). Stratification of the case-control population showed that 14% of the population would be at high risk, with an OR>2 (> 25% probability of developing breast cancer). Persons in this group would be candidates for individualized follow-up. Conclusions: The Polygenic Risk Score is an independent predictor of breast cancer risk that may help to select women at high risk, with a view to establishing individualised follow-up and treatment according to genetic risk

Correction: ANKK1 is found in myogenic precursors and muscle fibers subtypes with glycolytic metabolism.

[This corrects the article DOI: 10.1371/journal.pone.0197254.].

ANKK1 is found in myogenic precursors and muscle fibers subtypes with glycolytic metabolism.

Ankyrin repeat and kinase domain containing 1 (ANKK1) gene has been widely related to neuropsychiatry disorders. The localization of ANKK1 in neural progenitors and its correlation with the cell cycle has suggested its participation in development. However, ANKK1 functions still need to be identified. Here, we have further characterized the ANKK1 localization in vivo and in vitro, by using immunolabeling, quantitative real-time PCR and Western blot in the myogenic lineage. Histologic investigations in mice and humans revealed that ANKK1 is expressed in precursors of embryonic and adult muscles. In mice embryos, ANKK1 was found in migrating myotubes where it shows a polarized cytoplasmic distribution, while proliferative myoblasts and satellite cells show different isoforms in their nuclei and cytoplasm. In vitro studies of ANKK1 protein isoforms along the myogenic progression showed the decline of nuclear ANKK1-kinase until its total exclusion in myotubes. In adult mice, ANKK1 was expressed exclusively in the Fast-Twitch muscles fibers subtype. The induction of glycolytic metabolism in C2C12 cells with high glucose concentration or treatment with berberine caused a significant increase in the ANKK1 mRNA. Similarly, C2C12 cells under hypoxic conditions caused the increase of nuclear ANKK1. These results altogether show a relationship between ANKK1 gene regulation and the metabolism of muscles during development and in adulthood. Finally, we found ANKK1 expression in regenerative fibers of muscles from dystrophic patients. Future studies in ANKK1 biology and the pathological response of muscles will reveal whether this protein is a novel muscle disease biomarker.

The Addiction-Related Gene Ankk1 is Oppositely Regulated by D1R- and D2R-Like Dopamine Receptors.

The ankyrin repeat and kinase domain containing 1 (ANKK1) TaqIA polymorphism has been extensively studied as a marker of the gene for dopamine receptor D2 (DRD2) in addictions and other dopamine-associated traits. In vitro mRNA and protein studies have shown a potential connection between ANKK1 and the dopaminergic system functioning. Here, we have investigated whether Ankk1 expression in the brain is regulated by treatment with dopaminergic agonists. We used quantitative RT-PCR of total brain and Western blots of specific brain areas to study Ankk1 in murine brain after dopaminergic treatments. We found that Ankk1 mRNA was upregulated after activation of D1R-like dopamine receptors with SKF38393 (2.660 ± 1.035-fold; t: 4.066, df: 11, P = 0.002) and apomorphine (2.043 ± 0.595-fold; t: 3.782, df: 8, P = 0.005). The D2R-like agonist quinelorane has no effect upon Ankk1 mRNA (1.004 ± 0.580-fold; t: 0.015, df: 10, P = 0.9885). In contrast, mice treatment with the D2R-like agonists 7-OH-DPAT and aripiprazole caused a significant Ankk1 mRNA downregulation (0.606 ± 0.057-fold; t: 2.786, df: 10, P = 0.02 and 0.588 ± 0.130-fold; t: 2.394, df: 11, P = 0.036, respectively). With respect the Ankk1 proteins profile, no effects were found after SKF38393 (t: 0.54, df: 2, P = 0.643) and Quinelorane (t: 0.286, df: 8, P = 0.782) treatments. In contrast, the D2R-like agonist 7-OH-DPAT (±) caused a significant increment of Ankk1 in the striatum (t: 2.718, df: 7; P = 0.03) when compared to the prefrontal cortex. The activation of D1R-like and D2-R-like leads to opposite transcriptional regulation of Ankk1 by specific pathways.