Abstract 2778: Combination of DNA mismatch repair status and MACC1 expression in patients with stage II colon cancer: The BIOGRID studies
Authors: Rohr Ulrich-Peter , Herrmann Pia , Ilm Katharina , Zhang Hai , Lohmann Sabine , Reiser Astrid , Muranyi Andrea , Smith Janice , Burock Susen , Osterland Marc , Leith Katherine , Singh Shalini , Brunhoeber Patrick , Bowermaster Rebecca , Tie Jeanne , Christie Michael , Wong Hui-Li , Waring Paul , Shanmugam Kandavel , Gibbs Peter , Stein Ulrike S. 
Published: July 2017

Abstract
We have previously identified the gene Metastasis-Associated in Colon Cancer 1 (MACC1). MACC1 acts a prognostic biomarker for tumor progression, metastasis and patient survival for a broad variety of solid cancer types. Here we assessed if the MACC1 gene could separate stage II colon cancer patients with proficient mismatch repair (pMMR) into high- and low-risk groups who might benefit from or be spared adjuvant chemotherapy based on their prognosis. In the Charité 1 discovery cohort (n=61), MACC1 expression and MSI status were assayed by qRT-PCR in cryo-preserved tumors from CRC patients. MSS/MSI-low/MACC1-low tumors showed better survival vs. MSS/MSI-low/MACC1-high (P&lt;0.0001). Patients with MSS/MSI-low/MACC1-low tumors had a similar prognosis as patients with MSI-H tumors. The Charité 2 comparison cohort (n=40) was used to translate MACC1 qRT-PCR analyses to FFPE samples. MACC1 expression was significantly higher in metachronously metastasizing tumors linked to shorter relapse-free survival (RFS), independent of the tissue type analyzed (cryo-preserved or FFPE). Next we translated MACC1 mRNA levels from qRT-PCR to MACC1 protein levels from immunohistochemistry (IHC) by comparing them in consecutive FFPE tumor sections in the BIOGRID 1 training cohort (n=189) enriched for disease recurrence. Chemotherapy-naïve patients with unfavorable pMMR status separated into MACC1-high and -low groups. Better RFS was seen in the pMMR/MACC1-low vs. pMMR/MACC1-high group using MACC1 mRNA and protein expression. pMMR/MACC1-low expression was seen in 12% and 8% of patients by qRT-PCR and IHC; interestingly, they had the same favorable prognosis as the deficient MMR (dMMR) group. Prognostic and predictive findings from BIOGRID 1 were confirmed in the independent BIOGRID 2 validation cohort (n=306) unenriched for recurrence. Better RFS was again seen in chemotherapy-naïve patients in the pMMR/MACC1-low (6%) vs. pMMR/MACC1-high group. No patients with pMMR/MACC1-low phenotype had disease recurrence. Remarkably, pooling BIOGRID 1 and 2, 5-year RFS was 100% and thus significantly longer in the pMMR/MACC1-low vs. pMMR/MACC1-high group (P=0.037). Taken together, MACC1 expression, measured by qRT-PCR or IHC, differentiates patients with unfavorable pMMR status. Patients with stage II colon cancer and pMMR/MACC1-low tumor status have a similar favorable prognosis as those patients with dMMR status who might not benefit from adjuvant therapy.
Citation Format: Ulrich-Peter Rohr, Pia Herrmann, Katharina Ilm, Hai Zhang, Sabine Lohmann, Astrid Reiser, Andrea Muranyi, Janice Smith, Susen Burock, Marc Osterland, Katherine Leith, Shalini Singh, Patrick Brunhoeber, Rebecca Bowermaster, Jeanne Tie, Michael Christie, Hui-Li Wong, Paul Waring, Kandavel Shanmugam, Peter Gibbs, Ulrike S. Stein. Combination of DNA mismatch repair status and MACC1 expression in patients with stage II colon cancer: The BIOGRID studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2778. doi:10.1158/1538-7445.AM2017-2778