Molecular Characterization of Appendiceal Cancer and Comparison with Right-Sided (R-CRC) and Left-Sided Colorectal Cancer (L-CRC).

3611 Background: The natural history and prognosis of appendiceal adenocarcinomas (AA) differ from that of adenocarcinomas arising in other large bowel sites. Compared to CRC, AA has more peritoneal dissemination and worse outcome. Methods: A total of 184 samples from AA (42 pseudomyxoma peritonei (PMP), 70 mucinous (MU), 24 signet ring (SR) and 48 adenocarcinoma, NOS (NOS)), 1080 samples from L-CRC, and 994 from R-CRC were tested with Next-Generation Sequencing (NGS) on a 592-gene panel and immunohistochemistry (IHC). Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS, and PD-L1 by IHC (SP142). Statistical comparisons of AA and L-and R-CRC were done by Chi-square test. Results: High mutation rates in AA were seen in KRAS (55%), TP53 (40%), GNAS (31%), SMAD4 (16%), APC (10%), ARID1A (8%), RNF43 (7%), PIK3CA (6%) and BRAF (5%). MSI-high was seen in 2.2%, TML-high ( > = 17mut/MB) in 2.2% and PD-L1 expression in 2.8%. Compared to both L- and R-CRC, AA showed significantly higher mutation rates of GNAS, SMAD4 and lower TP53, APC, PIK3CA and FBXW7. Alterations associated with immune checkpoint inhibitor responses (MSI-high, TML-high, PD-L1) showed similar frequency in AA compared to L-CRC, but not R-CRC. Histopathological subtypes of AA showed different molecular patterns: PMP carried the highest KRAS (78%), GNAS (63%) and no PIK3CA or BRAF mutations. SR showed the lowest KRAS (17%) and APC (0%) mutation rates. MU was characterized by GNAS mutation rate of 36%. SR and PMP had no MSI-high or TML-high cases. Conclusions: Molecular characterization of AA revealed different characteristics compared with CRC; similarities were observed between AA and L-CRC despite anatomical distance, and molecular heterogeneity among histological subtypes were seen. These molecular differences may be critical to develop new treatments for appendiceal adenocarcinoma. % AA, % L-CRC, % R-CRC, % p values (AA vs. L) p values (AA vs. R) GNAS 31 1* 2* < 0.01 < 0.01 SMAD4 16 10* 11* 0.02 0.04 TP53 40 75* 66* < 0.01 < 0.01 APC 10 83* 70* < 0.01 < 0.01 PIK3CA 6 17* 22* < 0.01 < 0.01 FBXW7 3 9* 11* 0.04 0.01 MSI-high 2 3 15* < 0.01 TML-high 3 5 15* < 0.01 PD-L1 3 3 7* 0.048 BRAF 5 5 17* < 0.01 * p < 0.05 compared to AA