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 4020 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 pathological 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.

Progress on immuno-microenvironment and immune-related therapies in patients with pseudomyxoma peritonei

“…The predominant variants in PMP are Kirsten rat sarcoma viral oncogene homologue (encoded by KRAS ) and guanine nucleotide-binding protein alpha subunit (encoded by GNAS ), which exhibit an average mutation frequency of 66.7% and 49.5% for KRAS and GNAS , respectively 24 . The GNAS mutation is widely found in mucinous tumors, including mucinous tumors of the appendix and intraductal papillary mucinous neoplasms of the pancreas.…”

“…Developments in basic research technologies, including next-generation sequencing, have led to an in-depth study of gene mutation profiles in PMP, leading to important advances 24 , 125 . However, PMP has a unique TME that contains excess gelatinous mucus and sparse tumor cells, which increases the difficulty of cell extraction and subsequent oncologic research.…”