Genomic alterations of cerebrospinal fluid cell-free DNA in leptomeningeal metastases of gastric cancer.

BACKGROUND: Leptomeningeal metastases (LM) were rare in gastric cancer (GC), and GC patients with LM (GCLM) generally suffer from poor prognosis. Nevertheless, the clinical utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) was underinvestigated in GCLM. METHODS: We retrospectively studied 15 GCLM patients, and all patients had paired primary tumor tissue samples and post-LM CSF samples while 5 patients also had post-LM plasma samples. All samples were analyzed using next-generation sequencing (NGS), and the molecular and clinical features were correlated with clinical outcomes. RESULTS: CSF had higher mutation allele frequency (P = 0.015), more somatic mutations (P = 0.032), and more copy-number variations (P < 0.001) than tumor or plasma samples. Multiple genetic alterations and aberrant signal pathways were enriched in post-LM CSF, including CCNE1 amplification and cell cycle-related genes, and CCNE1 amplification was significantly associated with patients' overall survival (P = 0.0062). More potential LM progression-related markers were detected in CSF samples than in tumor samples, including PREX2 mutation (P = 0.014), IGF1R mutation (P = 0.034), AR mutation (P = 0.038), SMARCB1 deletion (P < 0.001), SMAD4 deletion (P = 0.0034), and TGF-beta pathway aberration (P = 0.0038). Additionally, improvement in intracranial pressure (P < 0.001), improvement in CSF cytology (P = 0.0038), and relatively low levels of CSF ctDNA (P = 0.0098) were significantly associated with better PFS. Lastly, we reported a GCLM case whose CSF ctDNA dynamic changes were well correlated with his clinical assessment. CONCLUSIONS: CSF ctDNA could more sensitively detect molecular markers and metastasis-related mechanisms than tumor tissues in GCLM patients, and our study sheds light on utilizing CSF ctDNA in prognostic estimation and clinical assessment in GCLM.

Clinical and Genomic Analysis of Patients with Short Survival after Surgery for Esophageal Squamous Cell Carcinoma.

BACKGROUND: This study aimed to investigate the prognosis of Chinese patients with esophageal squamous cell carcinoma (ESCC) after surgery and its correlation with genomic alterations (GAs) to identify potential prognostic markers. METHODS: The clinical information, pathological specimens, and follow-up information of 50 patients with stage II and III primary ESCC who were surgically resected in the Fourth Hospital of Hebei Medical University from January 2011 to December 2015 were collected in the present study. Based on overall survival (OS), these patients were divided into the short OS group (<3 years) and the long OS group (>4 years). GA detection was performed in patients with ESCC using next-generation sequencing. All categories of GAs were evaluated; the landscape of GAs in patients with ESCC was mapped; and the correlations between clinical characteristics, prognosis, and GAs were analyzed. RESULTS: There was no skew in the distribution of gender, smoking, and adjuvant therapy between the long OS group and the short OS group. A total of 372 GAs were detected in the 50 patients with ESCC, with 7 types of GAs, including insertions, deletions, and copy number variations, and missense mutations occurred most frequently, with a frequency of >50.0%. Tumor protein 53 (TP53; 50/50, 100%) was the most commonly mutated gene in the entire cohort followed by cyclin D1, cyclin-dependent kinase inhibitor 2A (CDKN2A), and fibroblast growth factor 19. More CDKN2A loss (p = 0.098) was detected in the short OS group than in the long OS group. The results of the multivariate analysis after adjustment for clinical factors showed a statistically significant difference in the CDKN2A loss between the two groups. Data obtained from The Cancer Genome Atlas for surgical ESCC revealed that the CDKN2A loss may be responsible for the poorer prognosis in postoperative patients with ESCC. CONCLUSION: In patients with progressive primary ESCC, the poor postoperative prognosis may be epiphenomenally associated with the CDKN2A loss.