Molecular profiling of appendiceal adenocarcinoma and comparison with right-sided and left-sided colorectal cancer

Purpose: The natural history and prognosis of appendiceal adenocarcinomas (AA) differ from those of adenocarcinomas arising in other large bowel sites. We aimed to compare the molecular profiles exhibited by AAs and CRCs, or between the histopathological subtypes of AA. Experimental Design: A total of 183 samples from AA (46 adenocarcinoma, not otherwise specified (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous adenocarcinoma (MU), and 27 signet ring cell carcinoma (SR)), 994 from right-sided colorectal cancer (R-CRC), and 1080 from left-sided CRC (L-CRC) were analyzed by next-generation sequencing (NGS) and immunohistochemical (IHC) markers. Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and PD-L1 by IHC. Results: We observed high mutation rates in AA samples for KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), and APC (10%). AA exhibited higher mutation rates in KRAS and GNAS, and lower mutation rates in TP53, APC, and PIK3CA (6%) than CRCs. PMP exhibited much higher mutation rates in KRAS (74%) and GNAS (63%), and much lower mutation rates in TP53 (23%), APC (2%), and PIK3CA (2%) than NOS. Alterations associated with immune checkpoint inhibitor response (MSI-high, TMB-high, PD-L1 expression) showed similar frequency in AA compared to L-CRC, but not R-CRC, and those of NOS were higher than other subtypes of AA and L-CRC. Conclusions:Molecular profiling of AA revealed different molecular characteristics than noted in R-CRC and L-CRC, and molecular heterogeneity between the histopathological subtypes of AA. Our findings may be critical to develop individualized approach for AA treatment.

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