Background: KRAS inhibitors exhibited promising efficacy as systemic therapy in KRAS G12C-mutant colorectal cancers (CRC) lately. Recent studies have revealed a number of genomic alterations related to acquired resistance to this type of drugs. The discovered resistant gene mutations include: 1. Novel acquired secondary KRAS mutations within the adagrasib-binding pocket such as Y96C, H95D/Q/R, R68S, 2. Activating mutations in genes (KRAS, BRAF, MAP2K1) MAPK signaling pathway, 3. Oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3, 4. Gene amplifications in KRAS, MET, MYC. Although found as acquired resistance mechanism to KRAS inhibitors, these genomic alterations might be primary or secondary in the setting of other type of therapies. Characterizing the natural distribution of these genomic alterations in cancer patients would contribute to clarifying the application potential of KRAS inhibitors. We herein performed a large-sample size analysis in Chinese colorectal cancer. Methods: A total of 9385 early-stage, late-stage, treated or treatment-naive CRC were included in this analysis. Calling of single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels), fusions and evaluation of tumor mutational burden (TMB) were performed using a wide panel next-generation sequencing (NGS) testing. Results: 43.4% (4069/9385) cases were KRAS-mutant in this cohort. KRAS G12C account for 5.8% (236/4069) in all KRAS-mutant CRC, and 15.7% (37/236) were harbored the above resistance genomic alterations. Fifteen KRAS G12C-mutant CRC were detected to have activating MAPK mutations, including G12D/V (n = 6), G13D (n = 3), Q61H (n = 6), NRAS Q61K (n = 3), MAP2K1 K57T (n = 3), and BRAF V600E (n = 4). Ten KRAS G12C-mutant CRC were detected to have oncogenic fusions, including TGFBR2-CACNA1D (n = 3), TPM4-ALK (n = 1), FGFR3-TACC3 (n = 1), ETV6-SNRPC (n = 1), KAZN-PAX7 (n = 1), NRG1-TTC12 (n = 1), TCF7L2-EWSR1 (n = 1) and ERBB2 arrangement (n = 2). It is noteworthy that a single case was with 5 gene arrangement events in 17q (ERBB2-ZPBP2, IKZF3-ERBB2, PGAP3-ERBB2, RARA-ERBB2, RARA-GRB7). Thirteen KRAS G12C-mutant CRC were detected to have amplifications in KRAS (n = 5), MYC (n = 5) and MET (n = 4) genes. TP53 (81%), APC (65%) and PIK3CA (32%) were the utmost frequent somatic mutational genes in this subgroup of CRC. In addition, all cases were microsatellite stable (MSS). Tumors harboring fusion variants showed relatively high TMB level in this cohort. Conclusions: Our analysis results indicate about 15% KRAS G12C-mutant Chinese CRC were probable resistant to KRAS^G12C inhibitor. One-third of these patients had co-existed oncogenic fusions and higher TMB levels, suggesting possibilities for other therapeutic choices.