Abstract A07: Transcriptional profiling confirms appendiceal adenocarcinoma is distinct from colorectal cancer, in vivo models needed
Authors: Shen John Paul , Chowdhury Saikat , Wu Ji , Fournier Keith , Kopetz Scott , Raghav Kanwal 
Published: June 2020

Abstract
Background: Despite mounting data revealing that appendiceal neoplasms are quite distinct from colorectal cancers (CRC), these rare tumors are most often treated with chemotherapy designed for CRC. The rarity of appendiceal neoplasms has made it difficult to conduct prospective or randomized clinical trials to guide therapy for these tumors; this issue is confounded by the fact that much heterogeneity exists between multiple histopathologic subtypes, including noninvasive mucinous neoplasms, mucinous and nonmucinous adenocarcinomas, carcinoids, goblet cell carcinoids, and signet ring cell carcinomas, as well as between high- and low-grade tumors. Recent large-scale genomic profiling efforts have identified frequent activating mutations in GNAS, a G-protein-coupled receptor (52% of mucinous adenocarcinomas, 72% of pseudomyxoma peritoneii (PMP), with a strong enrichment in low-grade tumors (χ2 p &lt; 0.0001). Currently available preclinical models of appendiceal tumor are very rare, and to the best of our knowledge models of low-grade, GNAS mutant appendiceal adenocarcinoma are nonexistent. Given that there is no effective systemic treatment for these low-grade tumors, here we try to address this need by generating in vivo and in vitro models of appendiceal cancer and coupling them with transcriptomic analyses to identify potential therapeutic targets in this molecularly distinct tumor type.
Methods: After prospectively obtaining informed consent, tumors from surgical resection of 13 patients with appendiceal adenocarcinoma were molecularly profiled with RNAseq and full-exome DNAseq. The histology and grade of these tumor was confirmed by expert pathology review and consisted of a mix of well (n = 4), moderate (n = 4), and poorly (n = 5) differentiated tumors. For the generation of in vivo models, fresh tumors were harvested and 0.5 cm3 tumor blocks were mixed with Matrigel and planted directly into the peritoneal cavity of nude mice by means of a 1-cm transverse abdominal incision performed under aseptic conditions.
Results: Unsupervised clustering of the transcriptomic profiles of the 13 appendiceal tumors revealed that tumors of similar grade clustered together. This was as expected given that histologic grade has been shown to be the most critical prognostic feature for appendiceal adenocarcinomas. When clustered with colorectal tumors from TCGA, the appendiceal tumors demonstrated much greater similarity to each other than the colorectal tumors, consistent with previous reports of significant differences in the somatic mutation profiles of appendiceal and colorectal tumors.
Conclusions: Appendiceal adenocarcinoma is a distinct disease from colorectal adenocarcinoma. High- and low-grade appendiceal tumors display marked differences in genomic and transcriptomic profiles; the creation of additional preclinical models of each will be critical for the development of appendix cancer-specific therapy.
Citation Format: John Paul Shen, Saikat Chowdhury, Ji Wu, Keith Fournier, Scott Kopetz, Kanwal Raghav. Transcriptional profiling confirms appendiceal adenocarcinoma is distinct from colorectal cancer, in vivo models needed [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A07.