The genomic landscape of appendiceal adenocarcinoma revealed by 855 whole exome sequences

Appendiceal adenocarcinoma (AA) represents a rare malignancy with a unique natural history characterized by peritoneal metastases without (except in rare instances) hematogenous spread. Despite this unique biology, it has historically been treated as an extension of colorectal adenocarcinoma (CRC). Given the growing data that chemotherapy designed for CRC is ineffective for many patients with AA, it is critical to understand the unique genomic landscape of AA.

Patients with AA (N=855) undergoing circulating tumor DNA monitoring using SignateraTM Molecular Residual Disease Test were included. Whole exome sequencing (WES) of tumor tissue and matched normal were used to identify patient-specific somatic mutations. Tumor mutational burden (TMB) and Microsatellite Instability (MSI) were analyzed. Gene ontology (GO) and KEGG network analysis were applied to identify significantly dysregulated canonical pathways. As a comparison group, colon (N=900) and rectal (N=900) cancer cases were analyzed.

The stage distribution for patients with AA was 50 (5.8%)/ 234 (27.4%)/ 164 (19.2%)/ 347 (40.6%)/ 60 (7.0%) for stage I/II/III/IV/unreported, respectively. A total of 1,091,024 variants were identified from the WES analysis of 855 tumor tissues, with a median of 47 variants per tumor. The vast majority of the variants were single nucleotide polymorphisms (SNPs) with rare insertions and deletions. AA had low TMB (median: 2.14 Muts/Mb) compared to rectal and colon (median: 3.61, 4.61 Muts/Mb, respectively) cohorts. Only 1.3% (11/855) of the AA tumors were MSI-High, significantly less frequent than in rectal (3.1%) and colon cancers (19.1%). The top five mutated genes in AA were KRAS (393, 45.9%), GNAS (209, 24.4%), TP53 (203, 24.2%), SMAD4 (108, 12.6%), and APC (80, 9.3%). Significant co-occurrence was observed for mutations, pairwise, KRAS-GNAS, KRAS-TP53, and SMAD4-TP53 (ORs 12.2, 3.5, 3.6, respectively, all q 40 single nucleotide variants demonstrated similarity to colon and rectal cohorts, despite the differences in mutation frequency of specific genes. Clock-like Signatures (SBS1 and SBS5) were observed in 413 cases (73.1%), followed by the Signatures of Mismatch Repair deficiency (SIG-MMR, SBS6 or SBS15) in 126 cases (22.3%). SIG-MMR tumors displayed significantly higher TMB (median 5.7 Muts/Mb, p < 0.001) and higher prevalence of MSI (8.7%) relative to tumors with Clock-like Signature.

This study represents the largest WES analysis to date of AA tumors. Importantly, while there are overlapping mutational signatures, suggesting similarity in the mutagenic process with CRC, distinct mutational differences between AA and CRC were noted.

The authors.

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S. Rivero-Hinojosa: Honoraria (Institution): Natera Inc. V. Aushev: Travel / Accommodation / Expenses: Natera, Inc.; Shareholder / Stockholder / Stock options: Natera, Inc.; Full / Part-time employment: Natera, Inc.. A. Jurdi: Shareholder / Stockholder / Stock options: Natera; Full / Part-time employment: Natera. M. Liu: Leadership role: Natera; Shareholder / Stockholder / Stock options: Natera; Full / Part-time employment: Natera. All other authors have declared no conflicts of interest.