The Promise of Epigenetics Research in the Treatment of Appendiceal Neoplasms

Abstract

Appendiceal cancers (AC) are a rare and heterogeneous group of malignancies. Historically, appendiceal neoplasms have been grouped with colorectal cancers (CRC), and treatment strategies have been modeled after CRC management guidelines due to their structural similarities and anatomical proximity. However, the two have marked differences in biological behavior and treatment response, and evidence suggests significant discrepancies in their respective genetic profiles. In addition, while the WHO classification for appendiceal cancers is currently based on traditional histopathological criteria, studies have demonstrated that histomorphology does not correlate with survival or treatment response in AC. Due to their rarity, appendiceal cancers have not been studied as extensively as other gastrointestinal cancers. However, their incidence has been increasing steadily over the past decade, making it crucial to identify new and more effective strategies for detection and treatment. Recent efforts to map and understand the molecular landscape of appendiceal cancers have unearthed a wealth of information that has made it evident that appendiceal cancers possess a unique molecular profile, distinct from other gastrointestinal cancers. This review focuses on the epigenetic landscape of epithelial appendiceal cancers and aims to provide a comprehensive overview of the current state of knowledge of epigenetic changes across different appendiceal cancer subtypes, highlighting the challenges as well as the promise of employing epigenetics in the quest for the detection of biomarkers, therapeutic targets, surveillance markers, and predictors of treatment response and survival in epithelial appendiceal neoplasms.

Keywords: appendiceal cancer; cancer biomarkers; epigenetic-specific biomarker; epigenetics; gastrointestinal cancer; precision oncology; translational research.

Figure 1

Illustration of 2019 WHO classification of epithelial appendiceal cancers [23]. LAMN: low-grade appendiceal mucinous neoplasm, HAMN: high-grade appendiceal mucinous neoplasm, PP/PYY: pancreatic polypeptide/peptide YY, MiNEN: mixed neuroendocrine–non-neuroendocrine neoplasm. Figure created with biorender.com, accessed on 19 July 2023.

Figure 2

Machine-learning- and genomics-based clustering of appendiceal mucinous adenocarcinoma and adenocarcinoma samples as described by [35], with subtype-defining mutations listed, including mutational frequencies, and mutations in epigenetic-related genes marked in blue. AC0-4: appendiceal cancer subtype 0–4 (nomenclature adopted from Ref. [35] for this figure). Permission to reproduce granted by Springer Nature (license number 5593061501581). Figure created with biorender.com, accessed on 19 July 2023.

Figure 3

Epigenetic regulatory gene mutations across appendiceal cancer subtypes extracted from the MSK-IMPACT platform created via cBioportal [49,50]. Appendiceal cancer subtypes: mucinous adenocarcinoma (N = 164), goblet cell adenocarcinoma (N = 72), and colonic-type adenocarcinoma (N = 37).

Figure 4

Major epigenetic pathways contributing to oncogenesis in appendiceal cancers and potential therapy-related targets. Ac: acetylation, DNMT: DNA methyltransferase, KAc: lysine acetylation, Me: methylation, P: phosphorylation, RTK: receptor tyrosine kinase, TSS: transcription start site, Ub: ubiquitination. Figure created with biorender.com, accessed on 19 July 2023.