Transcriptomic profiling of BRCA2 999del5 heterozygous cell lines

• Main Author: María Rose Bustos 1996-
• Other Authors: Háskóli Íslands
• Format: Thesis
• Language: English
• Published: 2020
• Subjects: Lífefna- og sameindalíffræði; Brjóstakrabbamein; Genarannsóknir; Kvenna; Iceland
• Online Access: http://hdl.handle.net/1946/35796

Breast cancer is the world's most common cancer diagnosed among women and it has been demonstrated that mutations in genes with roles in DNA repair pathways can vastly increase susceptibility for breast tumorigenesis. BRCA1 and BRCA2 are tumor suppressor genes which have roles in Homologous recombination, a DNA repair pathway that repairs double strand chromosomal breaks, and these genes are found mutated in multiple breast cancer cases. Approximately 7-8% of female breast cancer cases in Iceland are derived from a founder mutation in the BRCA2 gene (BRCA2 999del5), which is a 5bp deletion that leads to the formation of a stop codon. The truncated protein, encoded by the mutated BRCA2 999del5 gene, is extremely unstable and constantly degraded in cells which leads to loss of function. It has been demonstrated that genes that possess similar functions in DNA repair pathways, are upregulated in some cases where there is a complete loss of BRCA2 function. This indicates that these cells rely more heavily on alternative DNA repair pathways which minimize the hazardous effects that accompany the loss of BRCA2 function. However, this has only been examined in homozygous cases; that is when BRCA2 mutations are present in both alleles resulting in a complete loss of gene function. The objective of this study was to examine whether genes that possess similar functions as BRCA2 in DNA repair pathways are upregulated in cell lines that are heterozygous for the BRCA2 999del5 mutation. RNA sequencing data was analyzed in order to identify possible target genes and the results revealed multiple genes that are significantly overexpressed in the BRCA2 999del5 cell lines. If any of these particular genes are in fact compensating for reduced BRCA2 function, it is possible to examine if any of them is synthetic lethal with BRCA2, which could lead to novel drug targets for cancer treatments. Brjóstakrabbamein er algengasta krabbamein kvenna í heiminum. Sýnt hefur verið fram á að arfgengir gallar í DNA viðgerðargenum geta aukið ...