Molecular characterization of appendiceal cancer and comparison with right-sided (R-CRC) and left-sided colorectal cancer (L-CRC)

Authors:

Ryuma Tokunaga, Joanne Xiu, Curtis Johnston, Richard M. Goldberg, Philip A. Philip, Andreas Seeber, Alberto Puccini, Madiha Naseem, Francesca Battaglin, Martin D. Berger, Shivani Soni, Michelle McSkane, Afsaneh Barzi, Wu Zhang, Jimmy J. Hwang, Anthony F. Shields, John L. Marshall, Wolfgang M. Korn, Heinz-Josef Lenz

Background:

The natural history and prognosis of appendiceal adenocarcinomas (AA) differ from that of adenocarcinomas arising in other large bowel sites. Compared to colorectal cancer (CRC), AA has more peritoneal dissemination and worse outcome. Only a few reports exist on molecular differences between AA and CRC.

Methods:

A total of 183 samples from AA (46 adenocarcinoma, NOS (NOS), 66 pseudomyxoma peritonei (PMP), 44 mucinous (MU), 27 signet ring (SR) and), 994 samples from right-sided CRC (R-CRC), and 1080 from left-sided CRC (L-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 (SP142) by IHC. Statistical comparisons of AA and R-and L-CRC were done by Fisher’s exact 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%. When compared to both R- and L-CRC, AA showed significantly higher mutation rates of GNAS, SMAD4 and lower TP53, APC, PIK3CA, FBXW7, NRAS, and AMER1 (p < 0.05). 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 (74%), GNAS (63%) and no BRAF mutations. MU was characterized by GNAS mutation rate of 25%. SR showed the lowest KRAS (15%), PIK3CA (0%), and APC (0%) mutation rates. 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.

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