Targeted multiplex proteomics (TMP) and genomics of early-onset colorectal cancer (EO-CRC).

Abstract

97 Background: The incidence and mortality of early-onset colorectal cancer (EO-CRC) is on the rise. Consequently, there is an urgent unmet need to better understand their unique tumor biology to expand therapeutic options and improve clinical outcomes. Methods: Exploratory Targeted multiplex proteomics (TMP) and targeted 648 gene panel was performed on specimens from 35 patients with resected colon cancer diagnosed at age < = 40 years. TMP panel consisted of 72 proteins involved in differentiation, tumorigenesis, and response to chemotherapy, targeted therapy, and immunotherapy. Clinicopathologic and genomic data were also collected. Results: The median age of diagnosis was 33 years. The cohort included 15 male and 20 female patients. 20 (57%) had left-sided tumors and 6 (17%) had stage IV disease. Notable genomic alterations included mutations in: BRAF V600E (2/35); RAS (15/35); PIK3CA exon 9 or 20 (5/35); and ERBB2 (2/35). One patient exhibited ERBB2 amplification. 9/35 tumors were MSI-H. TMP analysis revealed overexpression of chemotherapy resistance proteins in several patients: ALDH1A1:16/35; ERCC1:1/35; GART:26/35; MDR1:9/35; MGMT:5/35; RRM1:6/35; TUBB3:1/35; TYMS:2/35; XRCC1:11/35. In contrast, some tumors exhibited elevated biomarkers of chemosensitivity: hENT1:8/35; DHFR:12/35; TYMP:15/35; OPRT:8/35; SLFN11:1/35; TLE:11/35; TOPO1:12/35; TOPO2A:1/35. Protein targets of cell signaling pathways were overexpressed in a number of tumors: CAT:16/35; CAV-1: 6/35; CBL:2/35; E-Cadherin: 19/35; HSP90A:16/35; HSP90B:18/35; MET:5/35; NQO1:18/35; paxillin:4/35; SRC:21/35; STAT3:11/35. Regarding EGFR and KRAS, none of the tumors exhibited elevated protein expression level. Furthermore, RAS mutational status did not correlate with the level of EGFR or KRAS protein expression. Antibody drug conjugate biomarkers were observed. HER2 overexpression was noted in one patient who had a confirmed ERBB2 amplification. Regarding immunotherapy targets, PDL-1 protein was not overexpressed in any tumor, whereas MSLN and TROP2 were elevated in 1/35 and 2/35 patients, respectively. Conclusions: TMP analysis of EO-CRC patients revealed marked heterogeneity in the expression of proteins involved in differentiation, tumorigenesis, and response to chemotherapy, targeted therapy, and immunotherapy. Differential protein expression may provide insight into therapeutic vulnerabilities for EO-CRC. Furthermore, the discordance between detected genomic alterations and protein expression levels highlights the complementary nature of genomic sequencing and TMP analysis.