Integrated clinico-molecular profiling of appendiceal adenocarcinoma reveals a unique grade-driven entity distinct from colorectal cancer

Abstract

Background Appendiceal adenocarcinoma (AA) is an orphan disease with unique clinical attributes but often treated as colorectal cancer (CRC). Understanding key molecular differences between AA and CRC is critical. Methods We performed retrospective analyses of AA patients (N = 266) with tumour and/or blood next-generation sequencing (NGS) (2013–2018) with in-depth clinicopathological annotation. Overall survival (OS) was examined. For comparison, CRC cohorts annotated for sidedness, consensus molecular subtypes (CMS) and mutations (N = 3283) were used. Results Blood-NGS identified less RAS/GNAS mutations compared to tissue-NGS (4.2% vs. 60.9%, P < 0.0001) and showed poor concordance with tissue for well-/moderately differentiated tumours. RAS (56.2%), GNAS (28.1%) and TP53 (26.9%) were most frequent mutations. Well/moderately differentiated tumours harboured more RAS (69.2%/64.0% vs. 40.5%) and GNAS (48.7%/32.0% vs. 10.1%) while moderate/poorly differentiated tumours had more TP53 (26.0%/27.8% vs. 7.7%) mutations. Appendiceal adenocarcinoma (compared to CRC) harboured significantly fewer APC (9.1% vs. 55.4%) and TP53 (26.9% vs. 67.5%) and more GNAS mutations (28.1% vs. 2.0%) (P < 0.0001). Appendiceal adenocarcinoma mutation profile did not resemble either right-sided CRC or any of the four CMS in CRC. High grade, but no mutation, was independently predictive of survival. Conclusion Integrated clinico-molecular profiling of AA identified key molecular drivers distinct from CRC. Appendiceal adenocarcinoma has a predominantly grade-driven biology that trumps mutations.

Current Management of Appendiceal Neoplasms

“…61 Most patients with signet ring cell tumors develop metastatic disease, all with peritoneal disease and only 10% occurring at distant sites. 62 Although AAs have a lower rate of KRAS and GNAS mutations (56% and 25%, respectively) compared with appendiceal MAN, 11,63,64 the rates are still higher than those seen in colorectal cancer. Mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) are also lower than those seen in colorectal cancer.…”

Targeted Next-Generation Sequencing Improves the Prognostication of Patients with Disseminated Appendiceal Mucinous Neoplasms

“…Similarly, Raghav et al published TP53 mutations were enriched in moderately-differentiated and poorly-differentiated mucinous adenocarcinomas, and TP53 mutational status correlated with poor patient OS after CRS-HIPEC. 33 However, mutations in TP53 were not an independent prognostic factor of OS when adjusted for AJCC/WHO grade. The authors therefore hypothesized that disseminated AMNs represents a network-based disease, arising not from a single dominant gene, but rather through dysregulation of multiple genomic pathways that converge to a speci c oncologic state.…”

Incidental Diagnosis of a High Grade Mucinous Neoplasm of the Appendix: A Case Report

“…Despite these unique clinical attributes, appendiceal neoplasms and colorectal carcinomas have been managed similarly due to their relative anatomic proximity and shared embryological origin. However, recent molecular profiling analyses using next-generation sequencing (NSG) have shown that appendiceal neoplasms have distinct molecular profiles and genetic mutations [6]. One study revealed high rates of KRAS and GNAS (28% vs 2%) mutations in appendiceal carcinoma compared to CRC [6,7].…”

“…However, recent molecular profiling analyses using next-generation sequencing (NSG) have shown that appendiceal neoplasms have distinct molecular profiles and genetic mutations [6]. One study revealed high rates of KRAS and GNAS (28% vs 2%) mutations in appendiceal carcinoma compared to CRC [6,7]. Appendiceal carcinoma was also associated with fewer APC (9% vs 55%) and TP53 (27 vs 67%) mutations compared to CRC 6.…”

“…Evidence-based guidelines for the management of appendiceal neoplasms are lacking and current treatment strategies mirror those for colorectal carcinoma (CRC). However, recent molecular profiling analyses have demonstrated that appendiceal neoplasms and CRC are distinct entities with separate driving genomic mutations [6,7]. Therefore, treatment strategies for appendiceal neoplasms should be targeted separately from CRC, even when these two disease processes are found concurrently.…”