Identification of germline genetic variants in miRNA genes targeting BRCA 1/2 genes and their role in chilean familial breast cancer risk : searching for novel findings

Mayo Glaser, Tomas Gabriel de
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Universidad del Desarrollo. Facultad de Medicina
Breast cancer (BC) is the most common cancer in women worldwide and the second most common malignancy as a whole, therefore constituting an important cause of death and a severe burden for public health systems. During the year 2012, it was estimated that 1.67 million new BC cases were diagnosed, which accounts for 25% of all new cancers and 15% of all cancer deaths among females. In Chile, BC is the first cause of death from cancer in women, followed by gallbladder and bile duct adenocarcinoma. Family history of BC (genetic predisposition) is one of the most important non-modifiable risk factors, being responsible for 5-15% of all cases and up to 25% of cases in women fewer than 30 years. Some familial BC cases present a dominant autosomal inheritance due to germline mutations in BRCA1/BRCA2 genes, which are responsible for up to 25% of hereditary BC cases. For the remaining 75%, other susceptibility alleles (moderate or low penetrance), could be responsible for a significant percentage of hereditary BC risk in BRCA1/BRCA2-negative families, as proposed by the current polygenic inheritance model of breast tumors. Examples of these genes are, PALB2, BARD1, ATM, CHECK2, RAD51 and XRCC3, among others. Nevertheless, 50 to 60 percent of familial BC cases carry an unknown genetic etiology. Thus, it is of vital importance to search for other novel gene candidates in order to better elucidate its genetic structure. As low penetrance susceptibility genes may account for the excess of this risk, recent research evidence strongly suggests that single nucleotide variants (SNVs) in pre-microRNA (pre-miRNAs and its boundaries) or mature microRNAs (miRNAs) genes are new possible candidates, as it is well established that they can function as oncogenes or tumor suppressor genes. In this milieu, several genetic epidemiological studies show associations between SNVs in miRNAs and BC risk, mainly through down regulation of DNA repair genes such as BRCA1/BRCA2 genes, which can be regulated by miRNAs targeting their mRNA sequences mostly at their three prime untranslated regions (3´UTRs). Considering that genetic variation is ethnic-specific, some of these studies have shown conflicting results when comparing the effect on BC risk for same variant within different populations. Currently, there are very few studies concerning variants in miRNA genes and BC risk in South American population, making the available information in this arena very scarce. Thus, the purpose of this doctoral thesis project is to identify novel genetic variants (such as SNVs, deletions or insertions) in 10 selected and experimentally validated pre-miRNA genes targeting BRCA1/BRCA2 genes. This will be carried out studying BRCA1/BRCA2-negative (also known as BRCAX) Chilean families with a strong family history for hereditary breast cancer disease. New identified variants will be searched in genetic databases and in the available literature in order to identify whether they correspond to previously described or non-previously described variants and if there are previous studies regarding these variants and familial BC disease. Also,bioinformatics analyses will be performed in order to evaluate the impact of the variant on the miRNA secondary structure and its physicochemical parameters, and comparing these results with the wild type (WT) of the same miRNA gene. Finally, using a TaqMan genotyping assay, selected variants according to specific criteria will be subjected to a case control study in order to assess if there is any association with an increased BC risk in the studied population.
Tesis presentada para optar al grado de Doctor en Ciencias Médicas.
Palabras clave
Cáncer , Mamas , Genes , 090036S