Grant: CIHR New Investigator

In North America, ovarian cancer is the leading cause of death due to gynecological malignancies and 75% of women with advanced ovarian cancer are not expected to survive beyond five years. High-grade serous ovarian cancers account for 70% of ovarian cancer cases. These cancers are thought to be chromosomally unstable, which means their genomes are highly susceptible to the introduction of large-scale genetic mutations and rearrangements on a continual basis. This assumption stems from the observation that the chromosomal makeup (karyotype) of ovarian cancers is extremely abnormal. Recent results from our group suggest that this presumption is incorrect. It seems that ovarian cancers undergo a period of chromosomal instability very early on as the cancer is being established which leads to the abnormal karyotype. At the time of disease diagnosis, however, these cancers have already reached a state of chromosomal stability. Thus, with respect to large-scale genomic changes, recurrences and metastases are almost identical to the original tumour. We have found, however, that small-scale changes corresponding to single letter DNA alterations continue to occur as tumours evolve. This finding represents a moment of recognition that 'the emperor has no clothes' with respect to the study of ovarian cancer. For this project, we will conduct an in-depth study of multiple tumour samples from 10 cases of high-grade serous ovarian cancer to determine the extent of genetic variability between tumours and try to discover how these cancers acquire chromosomal stability. We will also compare these results to early precursors of ovarian cancer from the fallopian tubes, to identify when chromosomal instability occurs in cancer evolution. The results of this work could reveal why a large proportion of ovarian cancers do not respond to treatment or develop treatment resistance and has important implications for the development of new treatments for this disease.