Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis in Appendiceal Pseudomyxoma Peritonei

Abstract Pseudomyxoma peritonei (PMP) is a rare malignant clinical syndrome with little known about the global mutation profile. In this study, whole-exome sequencing (WES) was performed in 49 appendiceal PMP to investigate mutation profiles and mutation signatures. A total of 4,020 somatic mutations were detected, with a median mutation number of 56 (1–402). Tumor mutation burden (TMB) was generally low (median 1.55 mutations/Mb, 0.12–11.26 mutations/Mb). Mutations were mainly enriched in the function of cancer-related axonogenesis, extracellular matrix–related processes, calcium signaling pathway, and cAMP signaling pathway. Mutations in FCGBP, RBFOX1, SPEG, RTK-RAS, PI3K-AKT, and focal adhesion pathways were associated with high-grade mucinous carcinoma peritonei. These findings revealed distinct mutation profile in appendiceal PMP. Ten mutation signatures were identified, dividing patients into mutation signature cluster (MSC) 1 (N = 28, 57.1%) and MSC 2 (N = 21, 42.9%) groups. MSC (P = 0.007) was one of the four independent factors associated with 3-year survival. TMB (P = 0.003) and microsatellite instability (P = 0.002) were independent factors associated with MSC 2 grouping. Taken together, our findings provided a broader view in the understanding of molecular pathologic mechanism in appendiceal PMP and may be critical to developing an individualized approach to appendiceal PMP treatment. Implications: This work describes exhaustive mutation profile of PMP based on WES data and derives ten mutation signatures, which divides patients into two clusters and serve as an independent prognostic factor associated with 3-year survival.