Proteogenomic characterization of primary colorectal cancer and metastatic progression identifies proteome-based subtypes and signatures
Atsushi Tanaka,
Makiko Ogawa,
Yihua Zhou,
Kei Namba,
Ronald C. Hendrickson,
Matthew M. Miele,
Zhuoning Li,
David S. Klimstra,
Patrick G. Buckley,
Jeffrey Gulcher,
Julia Y. Wang,
Michael H.A. Roehrl
Affiliations
Atsushi Tanaka
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Makiko Ogawa
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Yihua Zhou
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; ICU Department, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
Kei Namba
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
Ronald C. Hendrickson
Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Matthew M. Miele
Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Zhuoning Li
Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
David S. Klimstra
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Paige.AI, New York, NY, USA
Patrick G. Buckley
Genuity Science, Boston, MA, USA
Jeffrey Gulcher
Genuity Science, Boston, MA, USA
Julia Y. Wang
Curandis, New York, NY, USA
Michael H.A. Roehrl
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Corresponding author
Summary: Metastatic progression of colorectal adenocarcinoma (CRC) remains poorly understood and poses significant challenges for treatment. To overcome these challenges, we performed multiomics analyses of primary CRC and liver metastases. Genomic alterations, such as structural variants or copy number alterations, were enriched in oncogenes and tumor suppressor genes and increased in metastases. Unsupervised mass spectrometry-based proteomics of 135 primary and 123 metastatic CRCs uncovered distinct proteomic subtypes, three each for primary and metastatic CRCs, respectively. Integrated analyses revealed that hypoxia, stemness, and immune signatures characterize these 6 subtypes. Hypoxic CRC harbors high epithelial-to-mesenchymal transition features and metabolic adaptation. CRC with a stemness signature shows high oncogenic pathway activation and alternative telomere lengthening (ALT) phenotype, especially in metastatic lesions. Tumor microenvironment analysis shows immune evasion via modulation of major histocompatibility complex (MHC) class I/II and antigen processing pathways. This study characterizes both primary and metastatic CRCs and provides a large proteogenomics dataset of metastatic progression.
