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Theranostics 2022; 12(11):5138-5154. doi:10.7150/thno.73089 This issue Cite

Research Paper

Integrated multi-omics characterization of KRAS mutant colorectal cancer

Wei Chong^1,2,3,4, Xingyu Zhu^1,2,3,4, Huicheng Ren^1,2,3,4, Chunshui Ye^2,3,4, Kang Xu^1,2,3,4, Zhe Wang⁵, Shengtao Jia⁵, Liang Shang^1,2,3,4, Leping Li^1,2,3,4✉, Hao Chen^6✉

1. Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
2. Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
3. Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, China.
4. Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
5. Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
6. Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, 250021, China.

✉ Corresponding authors: Dr. Hao Chen, Ph.D, Clinical Research Center of Shandong University, Unit of Clinical Epidemiology, Qilu Hospital of Shandong University, Jinan, Shandong 250021, P.R. China. E-mail: qiluchenhaosdu.edu.cn, chenhao6938com. Prof. Leping Li, Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China. E-mail: lilepingcom.cn. More

Abstract

KRAS mutation is the most frequent oncogenic aberration in colorectal cancer (CRC). The molecular mechanism and clinical implications of KRAS mutation in CRC remain unclear and show high heterogeneity within these tumors.

Methods: We harnessed the multi-omics data (genomic, transcriptomic, proteomic, and phosphoproteomic etc.) of KRAS-mutant CRC tumors and performed unsupervised clustering to identify proteomics-based subgroups and molecular characterization.

Results: In-depth analysis of the tumor microenvironment by single-cell transcriptomic revealed the cellular landscape of KRAS-mutant CRC tumors and identified the specific cell subsets with KRAS mutation. Integrated multi-omics analyses separated the KRAS-mutant tumors into two distinct molecular subtypes, termed KRAS-M1 (KM1) and KRAS-M2 (KM2). The two subtypes had a similar distribution of mutated residues in KRAS (G12D/V/C etc.) but were characterized by distinct features in terms of prognosis, genetic alterations, microenvironment dysregulation, biological phenotype, and potential therapeutic approaches. Proteogenomic analyses revealed that the EMT, TGF-β and angiogenesis pathways were enriched in the KM2 subtype and that the KM2 subtype was associated with the mesenchymal phenotype-related CMS4 subtype, which indicated stromal invasion and worse prognosis. The KM1 subtype was characterized predominantly by activation of the cell cycle, E2F and RNA transcription and was associated with the chromosomal instability (CIN)-related ProS-E proteomic subtype, which suggested cyclin-dependent features and better survival outcomes. Moreover, drug sensitivity analyses based on three compound databases revealed subgroup-specific agents for KM1 and KM2 tumors.

Conclusions: This study clarifies the molecular heterogeneity of KRAS-mutant CRC and reveals new biological subtypes and therapeutic possibilities for these tumors.

Keywords: Colorectal cancer, KRAS mutation, Proteogenomics, Molecular subtype, Prognosis

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