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Updated: May 5, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Molecular Profiling of Low-Grade Appendiceal Mucinous Neoplasms (LAMN)
Julia Doll1,2, Katja Maurus1,2, Franziska Köhler3
1Institute of Pathology, University of Würzburg, Würzburg, Germany.
Abstract:
Low-grade appendiceal mucinous neoplasia (LAMN) represents a relatively rare tumor of the appendix typically diagnosed incidentally through appendectomy for acute appendicitis. In cases where perforation occurs, mucinous content may disseminate into the abdominal cavity, leading to the development of pseudomyxoma peritonei (PMP). The primary objective of this study was to elucidate the molecular characteristics associated with various stages of LAMN and PMP. DNA was extracted from LAMN, primary PMPs, recurrent PMPs, and adenocarcinomas originating from LAMN. The subsequent analysis involved the examination of mutational hotspot regions within 50 cancer-related genes, covering over 2800 COSMIC mutations, utilizing amplicon-based next-generation sequencing (NGS). Our findings revealed activating somatic mutations within the MAPK-signaling pathway across all tumors examined. Specifically, 98.1% of cases showed mutations in KRAS, while one tumor harbored a BRAF mutation. Additionally, GNAS mutations were identified in 55.8% of tumors, with no significant difference observed between LAMN and PMP. While LAMN rarely displayed additional mutations, 42% of primary PMPs and 60% of recurrent PMPs showed additional mutations. Notably, both adenocarcinomas originating from LAMN showed mutations within TP53. Furthermore, 7.7% (4/52) of cases exhibited a potentially targetable KRAS G12C mutation. In four patients, NGS analysis was performed on both primary PMP and recurrent PMP/adenocarcinoma samples. While mutations in KRAS and GNAS were detected in almost all samples, 50% of recurrent cases displayed an additional SMAD4 mutation, suggesting a notable alteration during disease progression. Our findings indicate two key points: First, mutations within the MAPK pathway, particularly in KRAS, are evident across all tumors, along with a high frequency of GNAS mutations. Second, progression toward PMP or adenocarcinoma is associated with an accumulation of additional mutations within common oncogenic pathways.
Insights
Molecular analysis of appendiceal mucinous neoplasia (LAMN) and pseudomyxoma peritonei (PMP) reveals common KRAS and GNAS mutations. Disease progression is linked to accumulating mutations in oncogenic pathways.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Low-grade appendiceal mucinous neoplasia (LAMN) is a rare appendix tumor.
- Perforation can lead to pseudomyxoma peritonei (PMP), a mucinous abdominal tumor.
- Understanding the molecular basis of LAMN and PMP progression is crucial.
Purpose of the Study:
- To investigate the molecular characteristics of LAMN, primary PMP, recurrent PMP, and LAMN-derived adenocarcinomas.
- To identify key genetic mutations driving the progression of these appendiceal neoplasms.
Main Methods:
- DNA extraction from various stages of LAMN and PMP.
- Next-generation sequencing (NGS) of hotspot regions in 50 cancer-related genes.
- Analysis of over 2800 COSMIC mutations.
Main Results:
- Activating MAPK-signaling pathway mutations, predominantly KRAS (98.1%), were found in all tumors.
- GNAS mutations occurred in 55.8% of tumors, with no significant difference between LAMN and PMP.
- Progression to PMP and adenocarcinoma correlated with an increased number of mutations, including TP53 and SMAD4.
Conclusions:
- MAPK pathway mutations (KRAS) and GNAS mutations are fundamental in LAMN and PMP development.
- Acquisition of additional mutations drives the progression from LAMN to PMP and adenocarcinoma.
- Targetable KRAS G12C mutations were identified in a subset of cases.
