Integrative Proteogenomic Characterization of Left-Sided and Right-Sided Colorectal Cancer

Abstract

Distinguishing characteristics have been found in the left-sided and right-sided colorectal cancer (CRC), which have different embryonic origins, molecular and clinical features. These result in differences in the efficacy of targeted therapy and immunotherapy. Multi-omics characterization, predicated upon tumor laterality, may facilitate a more precise and personalized approach to the treatment of patients with CRC. Encompassing whole-exome, proteomics, and phosphoproteomics sequencing, we conducted a comprehensive investigation of tumor and matched normal adjacent tissues from a total of 80 pairs of patients with CRC. Results revealed that the pathogenesis of left-sided CRC was predominantly associated with chromosomal instability, while right-sided CRC was primarily linked to microsatellite instability. Regarding the tumor microenvironment, left-sided CRC exhibited predominant microvascular endothelial cell proliferation, while right-sided CRC displayed enhanced MHC Class II-associated antigen presentation mediated by M1 macrophages. Additionally, the proportion of deficient mismatch repair that developed into microsatellite instability-high was observed to be lower in the left-sided CRC compared to the right-sided, indicating divergent DNA damage repair systems between laterality subtypes that contribute to differential immunotherapy efficacy. This integrated proteogenomic study provides a comprehensive and nuanced understanding of the molecular heterogeneity between left- and right-sided CRC, offering opportunities for optimizing these patients' treatment outcomes through tailored therapeutic strategies.

Keywords

colorectal cancer / left-sided / phosphoproteome / proteome / right-sided / whole-exome sequencing

References

[1] F. Bray, M. Laversanne, H. Sung, et al., “Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 74, no. 3 (2024): 229–263.

[2] H. Bingfeng, Z. Rongshou, Z. Hongmei, et al., “Cancer Incidence and Mortality in China,” Journal of the National Cancer Center 4, no. 1 (2024): 47–53.

[3] E. Dekker, P. J. Tanis, J. L. A. Vleugels, P. M. Kasi, and M. B. Wallace, “Colorectal Cancer,” Lancet 394, no. 10207 (2019): 1467–1480.

[4] M. S. Lee, D. G. Menter, and S. Kopetz, “Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes,” Journal of the National Comprehensive Cancer Network: JNCCN 15, no. 3 (2017): 411–419.

[5] J. M. Weiss, P. R. Pfau, and E. S. O'Connor, “Mortality by Stage for Right- Versus Left-Sided Colon Cancer: Analysis of Surveillance, Epidemiology, and End Results—Medicare Data,” Journal of Clinical Oncology 29, no. 33 (2011): 4401–4409.

[6] M. A. Aljehani, J. W. Morgan, L. A. Guthrie, et al., “Association of Primary Tumor Site with Mortality in Patients Receiving Bevacizumab and Cetuximab for Metastatic Colorectal Cancer,” JAMA Surgery 153, no. 1 (2018): 60–67.

[7] W. A. Messersmith, “Systemic Management of Colorectal Cancer,” Journal of the National Comprehensive Cancer Network: JNCCN 15, no. 5s (2017): 699–702.

[8] T. André, K. K. Shiu, T. W. Kim, et al., “Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer,” New England Journal of Medicine 383, no. 23 (2020): 2207–2218.

[9] S. Vasaikar, C. Huang, X. Wang, et al., “Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities,” Cell 177, no. 4 (2019): 1035–1049.e1019.

[10] H. Rodriguez, J. C. Zenklusen, L. M. Staudt, J. H. Doroshow, and D. R. Lowy, “The next Horizon in Precision Oncology: Proteogenomics to Inform Cancer Diagnosis and Treatment,” Cell 184, no. 7 (2021): 1661–1670.

[11] L. DeDecker, B. Coppedge, J. Avelar-Barragan, W. Karnes, and K. Whiteson, “Microbiome Distinctions Between the CRC Carcinogenic Pathways,” Gut Microbes 13, no. 1 (2021): 1854641.

[12] D. Mouradov, P. Greenfield, S. Li, et al., “Oncomicrobial Community Profiling Identifies Clinicomolecular and Prognostic Subtypes of Colorectal Cancer,” Gastroenterology 165, no. 1 (2023): 104–120.

[13] M. W. Su, C. K. Chang, C. W. Lin, et al., “Genomic and Metabolomic Landscape of Right-Sided and Left-Sided Colorectal Cancer: Potential Preventive Biomarkers,” Cells 11, no. 3 (2022): 527.

[14] H. Zhu, Y. Li, J. Guo, et al., “Integrated Proteomic and Phosphoproteomic Analysis for Characterization of Colorectal Cancer,” Journal of Proteomics 274 (2023): 104808.

[15] L. Magrin, D. Fanale, C. Brando, et al., “POLE, POLD1, and NTHL1: the Last but Not the Least Hereditary Cancer-predisposing Genes,” Oncogene 40, no. 40 (2021): 5893–5901.

[16] C. Palles, J. B. Cazier, K. M. Howarth, et al., “Germline Mutations Affecting the Proofreading Domains of POLE and POLD1 Predispose to Colorectal Adenomas and Carcinomas,” Nature Genetics 45, no. 2 (2013): 136–144.

[17] K. P. Hodel, M. J. S. Sun, N. Ungerleider, et al., “POLE Mutation Spectra Are Shaped by the Mutant Allele Identity, Its Abundance, and Mismatch Repair Status,” Molecular Cell 78, no. 6 (1166): 1166–1177.

[18] E. Domingo, L. Freeman-Mills, E. Rayner, et al., “Somatic POLE Proofreading Domain Mutation, Immune Response, and Prognosis in Colorectal Cancer: a Retrospective, Pooled Biomarker Study,” Lancet Gastroenterology & Hepatology 1, no. 3 (2016): 207–216.

[19] T. Takayama, K. Miyanishi, T. Hayashi, Y. Sato, and Y. Niitsu, “Colorectal Cancer: Genetics of Development and Metastasis,” Journal of Gastroenterology 41, no. 3 (2006): 185–192.

[20] J. Jen, H. Kim, S. Piantadosi, et al., “Allelic Loss of Chromosome 18q and Prognosis in Colorectal Cancer,” New England Journal of Medicine 331, no. 4 (1994): 213–221.

[21] S. Popat and R. S. Houlston, “A Systematic Review and Meta-Analysis of the Relationship Between Chromosome 18q Genotype, DCC Status and Colorectal Cancer Prognosis,” European Journal of Cancer 41, no. 14 (2005): 2060–2070.

[22] T. Watanabe, T. Kobunai, Y. Yamamoto, et al., “Chromosomal Instability (CIN) Phenotype, CIN High or CIN Low, Predicts Survival for Colorectal Cancer,” Journal of Clinical Oncology 30, no. 18 (2012): 2256–2264.

[23] S. Ogino, K. Nosho, N. Irahara, et al., “Prognostic Significance and Molecular Associations of 18q Loss of Heterozygosity: A Cohort Study of Microsatellite Stable Colorectal Cancers,” Journal of Clinical Oncology 27, no. 27 (2009): 4591–4598.

[24] S. Popat, D. Zhao, Z. Chen, et al., “Relationship Between Chromosome 18q Status and Colorectal Cancer Prognosis: a Prospective, Blinded Analysis of 280 Patients,” Anticancer Research 27, no. 1b (2007): 627–633.

[25] E. M. Stoffel, R. Erichsen, T. Frøslev, et al., “Clinical and Molecular Characteristics of Post-Colonoscopy Colorectal Cancer: a Population-Based Study,” Gastroenterology 151, no. 5 (2016): 870–878.e3.

[26] D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: the Next Generation,” Cell 144, no. 5 (2011): 646–674.

[27] J. Weng, S. Li, Z. Zhu, et al., “Exploring Immunotherapy in Colorectal Cancer,” Journal of Hematology & Oncology 15, no. 1 (2022): 95.

[28] H. Arai, A. Elliott, J. Xiu, et al., “The Landscape of Alterations in DNA Damage Response Pathways in Colorectal Cancer,” Clinical Cancer Research 27, no. 11 (2021): 3234–3242.

[29] A. Stemmer, O. Margalit, V. Serpas, et al., “Immunotherapy in Mismatch Repair-Deficient Metastatic Colorectal Cancer—Outcome and Novel Predictive Markers,” European Journal of Cancer 198 (2024): 113495.

[30] U. Gunnarsson, K. Strigård, S. Edin, et al., “Association Between Local Immune Cell Infiltration, Mismatch Repair Status and Systemic Inflammatory Response in Colorectal Cancer,” Journal of Translational Medicine 18, no. 1 (2020): 178.

[31] R. Beekhof, A. Bertotti, F. Böttger, et al., “Phosphoproteomics of Patient-Derived Xenografts Identifies Targets and Markers Associated With Sensitivity and Resistance to EGFR Blockade in Colorectal Cancer,” Science Translational Medicine 15, no. 709 (2023): eabm3687.

[32] B. Ponsioen, J. B. Post, J. R. Buissant des Amorie, et al., “Quantifying Single-Cell ERK Dynamics in Colorectal Cancer Organoids Reveals EGFR as an Amplifier of Oncogenic MAPK Pathway Signalling,” Nature Cell Biology 23, no. 4 (2021): 377–390.

[33] A. Huang, Y. Yang, J. Y. Shi, et al., “Mucinous Adenocarcinoma: a Unique Clinicopathological Subtype in Colorectal Cancer,” World Journal of Gastrointestinal Surgery 13, no. 12 (2021): 1567–1583.

[34] C. Luo, S. Cen, G. Ding, and W. Wu, “Mucinous Colorectal Adenocarcinoma: Clinical Pathology and Treatment Options,” Cancer Communications (London, England) 39, no. 1 (2019): 13.

[35] C. V. Rao, N. B. Janakiram, and A. Mohammed, “Molecular Pathways: Mucins and Drug Delivery in Cancer,” Clinical Cancer Research 23, no. 6 (2017): 1373–1378.

[36] R. Wang, T. Yamada, K. Kita, et al., “Transient IGF-1R Inhibition Combined With Osimertinib Eradicates AXL-Low Expressing EGFR Mutated Lung Cancer,” Nature Communications 11, no. 1 (2020): 4607.

[37] B. Song, S. H. Park, J. C. Zhao, et al., “Targeting FOXA1-Mediated Repression of TGF-β Signaling Suppresses Castration-resistant Prostate Cancer Progression,” Journal of Clinical Investigation 129, no. 2 (2019): 569–582.

[38] G. Ciriello, M. L. Gatza, A. H. Beck, et al., “Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer,” Cell 163, no. 2 (2015): 506–519.

[39] S. Shukla, J. Cyrta, D. A. Murphy, et al., “Aberrant Activation of a Gastrointestinal Transcriptional Circuit in Prostate Cancer Mediates Castration Resistance,” Cancer Cell 32, no. 6 (2017): 792–806.e7.

[40] C. Wang, T. Zhang, Q. Liao, et al., “Metformin Inhibits Pancreatic Cancer Metastasis Caused by SMAD4 Deficiency and Consequent HNF4G Upregulation,” Protein & Cell 12, no. 2 (2021): 128–144.

[41] A. Subramanian, P. Tamayo, V. K. Mootha, et al., “Gene Set Enrichment Analysis: a Knowledge-Based Approach for Interpreting Genome-wide Expression Profiles,” PNAS 102, no. 43 (2005): 15545–15550.

[42] A. Liberzon, A. Subramanian, R. Pinchback, H. Thorvaldsdóttir, P. Tamayo, and J. P. Mesirov, “Molecular Signatures Database (MSigDB) 3.0,” Bioinformatics 27, no. 12 (2011): 1739–1740.

[43] J. Y. Xu, C. Zhang, X. Wang, et al., “Integrative Proteomic Characterization of Human Lung Adenocarcinoma,” Cell 182, no. 1 (2020): e217.

[44] L. G. Almeida, N. J. Sakabe, A. R. deOliveira, et al., “CTdatabase: a Knowledge-Base of High-throughput and Curated Data on Cancer-Testis Antigens,” Nucleic Acids Research 37, no. Database issue (2009): D816–D819.

[45] S. V. Vasaikar, P. Straub, J. Wang, and B. Zhang, “LinkedOmics: Analyzing Multi-Omics Data Within and Across 32 Cancer Types,” Nucleic Acids Research 46, no. D1 (2018): D956–d963.

[46] M. J. Goldman, B. Craft, M. Hastie, et al., “Visualizing and Interpreting Cancer Genomics Data via the Xena Platform,” Nature Biotechnology 38, no. 6 (2020): 675–678.

[47] M. D. Wilkerson and D. N. Hayes, “ConsensusClusterPlus: a Class Discovery Tool With Confidence Assessments and Item Tracking,” Bioinformatics 26, no. 12 (2010): 1572–1573.

[48] Ö. Babur, A. Luna, A. Korkut, et al., “Causal Interactions From Proteomic Profiles: Molecular Data Meet Pathway Knowledge,” Patterns (N Y) 2, no. 6 (2021): 100257.

[49] D. Zeng, Z. Ye, R. Shen, et al., “IOBR: Multi-Omics Immuno-Oncology Biological Research to Decode Tumor Microenvironment and Signatures,” Frontiers in Immunology 12 (2021): 687975.

[50] K. Yoshihara, M. Shahmoradgoli, E. Martínez, et al., “Inferring Tumour Purity and Stromal and Immune Cell Admixture From Expression Data,” Nature Communications 4 (2013): 2612.

[51] D. Aran, Z. Hu, and A. J. Butte, “xCell: Digitally Portraying the Tissue Cellular Heterogeneity Landscape,” Genome Biology 18, no. 1 (2017): 220.

RIGHTS & PERMISSIONS

2026 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.