Genetic abnormalities and aberrant expression of genes involved in chromosome segregation and mitosis in patients with chromosomally unstable malignant soft tissue tumors haboring extensive somatic loss-of-heterozygosity (LOH).

Abstract

11576 Background: Malignant soft tissue tumor is a rare cancer with few therapeutic options. Recent genomic analysis of soft tissue sarcoma (STS) revealed a high degree of chromosomal instability (CIN) including genome-wide copy number alteration, aneuploidy, whole genome doubling and chromothripsis. In STS patients, we observed extensive somatic LOH, a hallmark of CIN, which is haploid of germline mutations/variants in cancer-related genes. CIN of STS genome implicates abnormalities in chromosome segregation and mitosis. So far, studies on this issue, however, have not been reported in STS patients. Methods: We recruited 155 patients with metastatic/recurrent malignant soft tissue tumors (135 female and 20 male, mean age 51 at analysis, 100 LMS, 19 LPS, 4 ESS, 3 UPS, 3 AS, 3 MPT, 3 GIST and others) with information of familial cancer burden. Whole exome sequencing and analysis were performed in both blood and tumor samples as described in 2018ASCO. KIF18A expression was assessed by immunohistochemistry. Results: Patients with tumors harboring less than 33% somatic LOH in a total of somatic and LOH mutations/variants in 595 COSMIC genes (n = 54) have a better prognosis than those (34-66%, n = 49, 67-100%, n = 52) with tumors harboring more LOH genes (5-year OS; 71% vs 52% or 46%, p = 0.0299, p = 0.0117, respectively). Neither TMB nor MSI status was associated with LOH. Of the genes involved in chromosome segregation and mitosis, we found that a family of ARHGAP genes which play a role in the spindle assembly and Aurora A kinase activation was frequently mutated in both tumor and germline genomes (n = 81 in a total of 155). Damaging ARHGAP mutations/variants in tumors are correlated with higher LOH values (54±3.4%, n = 81 vs. 39±3.3%, n = 74. mean±SE, p = 0.0021) and poor prognosis of patients (5-year OS; 58% n = 81 vs. 41% n = 74, p = 0.0098). We also found that elevated and robust expression of a mitotic kinesin KIF18A in tumors harboring higher LOH and/or damaging ARHGAP mutations/variants (n = 12) but not in lower LOH tumors without ARHGAP mutations/variants (n = 4). Conclusions: This study, for the first time, demonstrates that genetic abnormalities and aberrant expression of genes involved in chromosome segregation and mitosis in patients with malignant soft tissue tumors. The results reveal a novel target of drug discovery for incurable STS because CIN tumor cells are shown to be particularly vulnerable to KIF18A inhibition, while somatic, diploid cells are not.