Identification of Mutation Profiles in Ovarian Cancer and Clinically Actionable Biomarkers

Résumé du livre

Sixty-five percent of the 22,000 women diagnosed with ovarian cancer in the United States this year will succumb to the disease because most women are diagnosed after the disease is in its advanced stages. The survival rate could be improved if molecular tools were able to detect the disease in its early stages and treatment options could be tailored to the individual patient's molecular make up. The goal of this project is to perform mutation profiling in paired primary and metastatic tumors of the ovary to identify key signatures. In addition, borderline ovarian tumors, tumors that are benign yet it has been estimated that 20% advance to malignancy, were also analyzed and compared to the primary and metastatic profile identified. In this study, cancer related gene targets were simultaneously amplified, sequenced, quantified and analyzed using the Ion TorrentTM sequencer. This study identified nine common single nucleotide polymorphisms (SNPs) in the primary and metastatic tumors with a frequency of 79% or more generating a profile that may indicate a predisposition for ovarian cancer. Among these nine variants was a SNP in a tumor suppressor gene which was present in 100% of the tumors and 60% in the general population. The borderline tumors were interrogated for these nine SNPs and found to also have a high frequency of these variants. However, the primary and metastatic cancer tumors also had an additional mutation in the tumor suppressor gene at varying locations which were predicted to be deleterious and cancer driver variants unlike the borderline tumors. The borderline tumors, on the other hand, had mutations in the Ras/Raf/MEK/ERK cell proliferation pathway in key oncogenes. Mutations at these identified sites have been found to be carcinogenic in other tissues. In addition, variants in common between the borderline and malignant tumors, particularly in the KDR gene, give insight into which borderline tumors may be likely to progress to malignancy. These results indicate a possible role for these variants in ovarian tumorigenesis and potential identification of molecular biomarkers for early detection of ovarian cancer and targeted treatment of the disease.