Asociación entre variación germinal en mirnas y susceptibilidad al cáncer de mama familiar en población chilena y su rol en la transformación celular
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Morales-Pison, Sebastian MoralesAbstract
In Chile, breast cancer (BC) has the highest cancer mortality rate in women (16.6/100,000 women). The main risk factor for BC development is genetic predisposition. Mutations in the BRCA1/2 genes are responsible for 40–50% of familial BC risk on average. It has been pro-posed that other so-called moderate- and low-penetrance susceptibility alleles could be re-sponsible for the remaining 50% of BRCA1/2-negative familial BC cases. Recent evidence s...
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In Chile, breast cancer (BC) has the highest cancer mortality rate in women (16.6/100,000 women). The main risk factor for BC development is genetic predisposition. Mutations in the BRCA1/2 genes are responsible for 40–50% of familial BC risk on average. It has been pro-posed that other so-called moderate- and low-penetrance susceptibility alleles could be re-sponsible for the remaining 50% of BRCA1/2-negative familial BC cases. Recent evidence suggests that microRNAs (miRNAs) are candidate low-penetrance genes for BC susceptibil-ity. Various studies have shown that miRNAs are aberrantly expressed in cancer and that the presence of genetic variants in the pre-miRNA or mature miRNA sequence could be the cause of their dysregulation. Given the above, this study assessed the association of SNP rs4541843, located in the pri-miR-182, with risk of familial BC using a case-control design. Furthermore, BC cell lines were used to evaluate the functional roles of SNPs rs6505162 (pre-miR-423), rs895819 (pre-miR-27a), and rs4541843 in mammary tumorigenesis. The association results showed that the rs4541843 T allele was linked to increased risk of devel-oping BC in BRCA1/2-negative Chilean patients. This is the first study to evaluate an associ-ation between rs4541843 and any human pathology. A previous study determined that the rs6505162 A allele increased BC risk in a Chilean population and that the rs895819 G allele had a protective effect, reducing the risk of developing BC. Here, the functional study based on this concept showed that the rs6505162 A allele increased cell proliferation, migration, and invasion. In addition, the A allele promoted resistance to cisplatin and decreases apopto-sis, confirming its role as a risk allele. On the other hand, the rs895819 G allele was found to function differentially in mammary tumorigenic processes depending on BC subtype, partic-ipating as a tumor suppressor in the triple-negative BC subtype but as an oncogene in the luminal A subtype. Finally, it was observed that the rs4541843 C allele had an oncogenic role, increasing cell proliferation, migration, and invasion, as well as promoting resistance to cisplatin and decreasing apoptosis. These results indicate that the risk allele was the C allele, not the T allele. These findings are the first to characterize the functional role of SNPs rs6505162, rs895819, and rs4541843 in mammary tumorigenesis.
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Date de publicación
2022Academic guide
Jara Sosa, Lilia Elena
Contreras, Héctor Ruberly
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