The Link Between Genomic Instability ,Abnormal Meiotic/ Kinetochore Gene Expression and Tumor Formation

Introduction: Solid tumors have a high propensity towards genomic or chromosomal instability (CIN). CIN is defined as the ability of cells to constantly change their genome, with a large cell-to-cell variability in genome content. CIN tumors are more aggressive and often harder to treat and in general have worse prognosis than non-CIN tumors. It was previously shown that many tumors express high levels of genes which participate in meiosis, the overexpression of meiosis- specific genes could in principle cause the tumor to become CIN. The same is claimed about genes which encode kinetochore components- the machinery responsible for chromosome segregation. This work aims to investigate if indeed the mis-expression of meiosis and kinetochore genes drives CIN in cancer.

Materials and Methods: Initially, a thermodynamic-based theoretical approach - suprisal analysis, was used on existing TGCA tumor datasets and results from suprisal analysis were further explored using wet lab techniques.

Results: From our suprisal analysis, we were able to show that highly expressed meiotic and kinetochore genes were enriched in the dominant processes of cancer types, namely Breast cancer, Bladder cancer and Stomach cancer. In other types of cancer (Colorectal cancer, Head and Neck and Cervical cancer) there was less enrichment of meiotic and kinetochore genes. We also found that Bladder, Breast and stomach cancer have high CNVs compared to other types of cancer and processes with altered meiosis and kinetochore genes compare to the patients with low lCNVs. This result points to a high correlation between over-expressing meiosis and kinetochore genes and genome instability. Moreover, overexpression of Dmc1 in HCT116 cell line caused abnormal cell division and defective spindle formation.

Conclusion: Our results suggest that overexpression of both meiosis and kinetochore genes may drive genomic instability and cancer progression. Studies are underway in our laboratory, aiming to validate this hypothesis experimentally.