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Published on: August 24, 2019
Molecular and clinicopathological features of appendiceal mucinous neoplasms
Yuka Yanai1, Tsuyoshi Saito2,3, Takuo Hayashi1
1Department of Human Pathology, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
Abstract:
Appendiceal mucinous tumors (AMTs) include low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs). We collected 51 AMT samples (LAMN: 34, HAMN: 8, MAC: 9). Three of the eight HAMN cases contained LAMN components, and four out of nine MAC cases contained LAMN and/or HAMN components within the tumor. A next-generation sequencing (NGS) cancer hotspot panel was used to analyze 11 pure LAMN, 4 HAMN, and 3 MAC cases. The results revealed KRAS and GNAS as the most frequently mutated genes. Sanger sequencing was then performed to detect KRAS, GNAS, and TP53 mutations in the remaining 31 cases and RNF43 mutations in all cases. KRAS/GNAS and TP53 mutations occurred exclusively in pure LAMNs; however, five LAMN cases had mutations in both KRAS and GNAS. RNF43 mutations almost exclusively occurred with KRAS/GNAS mutations in pure LAMNs. In MAC and HAMN, KRAS/GNAS mutation status was nearly preserved between lower-grade areas. Most of the detected RNF43 mutations was missense type. RNF43 mutations were detected in both components of MAC with lower-grade area; however, RNF43 mutations detected in these two lesions were entirely different. RNF43 mutations were detected in only one of the eight HAMN patients, which was the sole case without pseudomyxoma peritonei (PMP). None of the four MAC patients with RNF43 mutation showed PMP. These findings suggest that RNF43 mutations occur at a later stage of MAC development and do not associate with PMP. Furthermore, a gradual transition from LAMN to MAC via HAMN could be considered.
Insights
Genetic mutations in appendiceal mucinous tumors (AMTs) like KRAS, GNAS, and TP53 are linked to low-grade neoplasms. RNF43 mutations appear later in high-grade mucinous appendiceal neoplasms and mucinous adenocarcinomas, and are not associated with pseudomyxoma peritonei.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Pathology
Background:
- Appendiceal mucinous tumors (AMTs) encompass a spectrum from low-grade (LAMN) to high-grade (HAMN) and mucinous adenocarcinomas (MAC).
- Understanding the molecular drivers of these tumor types is crucial for diagnosis and treatment.
- Previous studies have identified key genetic alterations in gastrointestinal cancers, but specific mutational profiles for AMTs require further elucidation.
Purpose of the Study:
- To investigate the genetic landscape of appendiceal mucinous tumors (AMTs) using next-generation sequencing (NGS) and Sanger sequencing.
- To identify specific mutations associated with different grades of AMTs (LAMN, HAMN, MAC).
- To explore the role of RNF43 mutations in tumor progression and their association with pseudomyxoma peritonei (PMP).
Main Methods:
- Analysis of 51 appendiceal mucinous tumor (AMT) samples, including low-grade mucinous appendiceal neoplasms (LAMNs), high-grade mucinous appendiceal neoplasms (HAMNs), and mucinous adenocarcinomas (MACs).
- Next-generation sequencing (NGS) cancer hotspot panel applied to a subset of pure LAMN, HAMN, and MAC cases.
- Sanger sequencing used for KRAS, GNAS, TP53, and RNF43 mutations in remaining and all cases, respectively.
Main Results:
- KRAS and GNAS were the most frequently mutated genes, primarily in pure LAMNs, with some LAMNs exhibiting both mutations.
- TP53 mutations were also exclusive to pure LAMNs.
- RNF43 mutations were predominantly found in pure LAMNs alongside KRAS/GNAS mutations, and in MAC, but were absent in most HAMNs and not associated with PMP.
Conclusions:
- A gradual transition from LAMN to MAC via HAMN is supported by the observed mutational patterns.
- RNF43 mutations may indicate a later stage in mucinous adenocarcinoma development and are not linked to pseudomyxoma peritonei.
- The distinct mutational profiles of LAMN, HAMN, and MAC highlight potential molecular differences driving tumor progression.
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