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Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis
Yu-Lin Lin1, Jun-Qi Zhu2, Rui-Qing Ma3
1Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
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.
Insights
This study reveals the mutation profile of appendiceal pseudomyxoma peritonei (PMP) using whole-exome sequencing. Distinct mutation signatures were identified, with mutation signature clusters impacting patient survival.
Area of Science:
- Oncology
- Genomics
- Molecular Pathology
Background:
- Pseudomyxoma peritonei (PMP) is a rare malignancy with an incompletely understood global mutation profile.
- Investigating the molecular landscape of appendiceal PMP is crucial for understanding its pathogenesis and developing targeted therapies.
Purpose of the Study:
- To comprehensively analyze the mutation profile and identify mutation signatures in appendiceal PMP using whole-exome sequencing (WES).
- To explore the association between mutation profiles, mutation signatures, and clinical outcomes, including survival.
Main Methods:
- Whole-exome sequencing (WES) was performed on 49 samples of appendiceal PMP.
- Somatic mutations, tumor mutation burden (TMB), and mutation signatures were analyzed.
- Statistical analyses were conducted to identify associations with clinical parameters and survival.
Main Results:
- A total of 4,020 somatic mutations were detected, with a generally low tumor mutation burden (TMB).
- Mutations were enriched in pathways related to axonogenesis, extracellular matrix, calcium signaling, and cAMP signaling.
- Ten distinct mutation signatures were identified, leading to the classification of patients into two mutation signature clusters (MSCs).
- MSC grouping, TMB, and microsatellite instability were independently associated with 3-year survival.
Conclusions:
- This study provides a detailed molecular profile of appendiceal PMP, highlighting distinct mutation patterns.
- Mutation signatures serve as independent prognostic factors, offering potential for individualized treatment strategies.
- Further understanding of the molecular pathology of PMP can guide the development of novel therapeutic approaches.
