使用 FusionPlus Hi-C 对存档的卵巢和子宫癌肉瘤 FFPE 组织进行全基因组检测以确定 HRD 状态

Genomic rearrangements such as gene fusions and copy number variation are chromosomal abnormalities important in cancer, including diagnosis and treatment. Approximately 50% of ovarian cancers involve homologous recombination deficiency with characteristic genomic rearrangements. HRD tumors have been shown to respond well to PARPi treatments. PARPi are an approved treatment for cancers known to have abnormalities in DNA repair mechanisms including ovarian cancers. Ovarian and uterine carcinosarcoma is a rare and aggressive form of gynecologic cancer with few diagnostic and treatment options. Genetic testing and HRD assays are invaluable in cancer diagnosis and treatment. Molecular testing in lung and other solid tumors has led to the identification of driver mutations that can be targeted by new therapeutics. Detection of these fusion proteins by RNA sequencing is the current gold standard but evidence suggests that fusions are still missed for various reasons. This study aims to improve detection rate of targetable fusions and rearrangements in solid tumors, ovarian and uterine carcinosarcoma specifically, using a new method called Hi-C sequencing. The Hi-C assay has been promising in locating genomic abnormalities in various types of cancer. Hi-C sequencing is a whole genome DNA-sequencing assay for detection of structural variation based on unique Hi-C chemistry which leverages sequencing of linked pairs of reads which occur nearby one another in 3-dimensional and linear space, from FFPE samples. Linking reads amplifies the rearrangement signal by giving it many more read pairs spanning the breakpoint and also overcoming masked fusions resulting from breakpoints in non-unique sequences. This method is useful for a variety of specimen types and preservation methods as well as archival periods. Hi-C testing works well for formalin fixed paraffin embedded tissue which is important for solid tumor testing such as with carcinosarcoma. We used Hi-C testing on archived FFPE ovarian and uterine carcinosarcoma tissue to determine if it could be beneficial in future cases improving prognosis, and therapeutic choices, particularly in identifying HRD tumors and the use of PARPi treatments. Our data has shown that 7 out of 18 samples tested had aberrations involving genes potentially involved in HRD. These genomic aberrations included significant rearrangements, gene fusions, and loss-of-function in several genes involved in HRD including RAD51B, CHEK2, and FANCA1. These data suggest that Hi-C testing could be a valuable tool in the molecular classification of solid tumor cancers and provide earlier more thorough diagnosis and more precise treatment options for gynecologic carcinosarcoma with the notable benefits of being faster and lower cost, possibly advancing clinical research with the discovery of novel biomarkers and therapeutic targets.