THE ROLE OF MODIFIER GENES IN EMBRYO AND TUMOR DEVELOPMENT - BRCA1 AS A MODEL

The Breast Cancer 1 protein (BRCA1) is a tumor suppressor involved in essential cellular functions necessary for genome integrity and embryonic development. New evidence demonstrates that the crosstalk between BRCA1, MET and specific inherited driver modifier genes (IDMGs) plays a significant role in embryo and tumor development and response to therapy.

We studied the effect of the genetic background on homozygous BRCA1 induces embryonic lethality. Embryonic ultrasound follow-up demonstrates early embryonic death in the 01XC4 homozygous BRCA1 line. Pathological analysis indicates that all the empty sacs contain placenta and no evidence of erythrocyte. Dead newborn mice developed severe hypoxia and expanded facial space. In line 01XC9 line, most of empty sacks have erythrocytes signifying that embryonic lethality occurred at an advanced pregnancy stage. The dead newborn mouse showed enlargement in the neural tube. These results demonstrate that the genetic background profoundly affects embryo development. Using Pathomics AI we studied the difference in the nuclear morphology induced in the tumor, showing a dramatic effect of BRCA1 and its modifiers.
To study the role of BRCA1, we established a CRISPR/Cas9 KO/KD. The cells were subjected to single cell morphokinetic analysis TASC developed in our lab. The results demonstrate that BRCA1 plays a significant role in cell motility and morphology. To our surprise when the cells express BRCA1 gene at a low level of 10-30% the motility of the cells increases, and when the expression levels of BRCA1 is eliminated the motility of the cells decreases (Bell Shape). These results can explain what drives BRCA1 mutation carriers to differentially develop metastasis
Meta-analyses of human BRCA1-candidate modifier genes yield 508 published candidate genes. Several knowledge-based bioinformatics analyses and survival analyses were utilized to rank these genes` importance in BC progression. Several IDMGs such as EPCAM (pv=0.0012) serve as prognostic factors. Seven more genes also serve as an excellent prognostic factor together with BRCA1. The molecular mechanism altered by the IDMGs and the potential as a novel target for therapy was studied using PPI analysis and graphical AI. Using graphic AI, we also developed a tool to personalize treatment based on the RP coding genes.

These results demonstrate the prominent role of IDMGs on the BRCA1 pathological mutation-induced tumorigenesis and as targets for risk assessment prevention and precision therapy.