Genomic Instability in Cerebrospinal Fluid Cell-Free DNA Predicts Poor Prognosis in Solid Tumor Patients with Meningeal Metastasis

SIMPLE SUMMARY: We established a genomic instability score using unfiltered sequencing data from meningeal metastasis (MM) cell-free circulating tumor DNA (ctDNA) samples and found that substantial genomic instability (GI) was present in cerebrospinal fluid ctDNA rather than plasma ctDNA, implying that MM lesions have a significantly increased GI status compared to primary tumors or extracranial metastatic lesions, which may suggest tumor clonal evolution. We also found that high GI status was an independent poor prognostic factor in lung adenocarcinoma MM patients, including meningeal metastasis-free survival (MFS) and overall survival (OS). Considering that genomically unstable tumors are more sensitive to PARP inhibitors, targeting GI alone or in combination with conventional therapy may be a promising treatment strategy for solid tumor patients with MM. ABSTRACT: Genomic instability (GI), which leads to the accumulation of DNA loss, gain, and rearrangement, is a hallmark of many cancers such as lung cancer, breast cancer, and colon cancer. However, the clinical significance of GI has not been systematically studied in the meningeal metastasis (MM) of solid tumors. Here, we collected both cerebrospinal fluid (CSF) and plasma samples from 56 solid tumor MM patients and isolated cell-free ctDNA to investigate the GI status using a next-generation sequencing-based comprehensive genomic profiling of 543 cancer-related genes. According to the unfiltered heterozygous mutation data-derived GI score, we found that 37 (66.1%) cases of CSF and 3 cases (6%) of plasma had a high GI status, which was further validated by low-depth whole-genome sequencing analysis. It is demonstrated that a high GI status in CSF was associated with poor prognosis, high intracranial pressure, and low Karnofsky performance status scores. More notably, a high GI status was an independent poor prognostic factor of poor MM-free survival and overall survival in lung adenocarcinoma MM patients. Furthermore, high occurrences of the co-mutation of TP53/EGFR, TP53/RB1, TP53/ERBB2, and TP53/KMT2C were found in MM patients with a high GI status. In summary, the GI status in CSF ctDNA might be a valuable prognostic indicator in solid tumor patients with MM.