Chongfan Technology
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04
2024
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08
Cancer Res | Ding Chen/Hou Yingyong/Yu Wei/Liu Chenying Cooperation Reveals Molecular Characteristics of Different Progressive Stages of Colorectal Cancer!
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Colorectal cancer (CRC) is the second most common malignancy in the world. Analyzing the changes that occur during the progression of colorectal cancer can provide insight into the molecular mechanisms that drive the development of colorectal cancer and identify improved treatment strategies.
On June 11, 2024, Fudan University Ding Chen, Hou Yingyong, Yu Wei and Shanghai Jiaotong University Liu Chenying jointly communicatedCancer ResearchPublished online entitled“Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression”research paper, the studyProvides an information resource for understanding the driving events at different stages of CRC and identifying potential therapeutic targets.
The study conducted a comprehensive multi-omics analysis of 435 tumor samples from 148 colorectal cancer (CRC) patients, including non-tumor (NT), intraepithelial neoplasia (IEN), infiltrating (IFT), and advanced CRC (A-CRC) stages. Proteogenomic analysis revealed that KRAS and BRAF mutations are mutually exclusive and that oxidative phosphorylation is elevated at the IEN phase. Chr17q deletion and Chr20q increase are also mutually exclusive, occurring mainly in the IEN and IFT phases, respectively, and affecting the cell cycle. TP53 mutations are common in stage A- CRC and are associated with the tumor microenvironment, including increased stiffness of the extracellular matrix and interstitial infiltration. CRC profiling based on CMS and CRIS classifications revealed progression pathways for each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Further comparison of location-based CRC molecular signatures indicated that the chr10q23.31 amplification ANKRD22 enhanced glycolysis in right CRC.The AOM/DSS-induced mouse CRC carcinogenesis model showed that DDX5 deletion caused by chr17q deletion promoted the development of CRC, which is consistent with the results of patient samples.
Colorectal cancer (CRC) is a common malignant tumor with the second and third highest morbidity and mortality, respectively.Colorectal cancer is highly heterogeneous, characterized by the accumulation of multiple mutations and complex carcinogenic progression, which brings obstacles to the standardization of surgical techniques and more effective systemic treatment of early and advanced disease. In general, CRCs evolve through the adenoma-carcinoma sequence and are divided into early CRCs (such as stage T1) and advanced CRC (known in the study as stage A- CRC), including stages T2, T3, and T4. Specifically, T1 staging can be divided into surface neoplasia staging (IEN stage in the study) and invasive cancer staging (IFT stage in the study). According to the depth of invasion, IFT stage is divided into lamina propria, muscularis mucosa and submucosa stage (the study named LP stage, MM stage and SM stage respectively). In recent years, the research progress has realized the early detection of the quality of life of CRC patients, and significantly improved the overall survival rate (>90%), revealing the dominant mutations and key events may help to explore the molecular mechanism of CRC carcinogenesis, and provide accurate medication for CRC clinical.However, in practice, due to the complexity of colorectal cancer development and the small tissue sample size at different stages of colorectal cancer, delineating the multi-omics molecular landscape and the critical transmission events from normal or curable disease to progressively fatal disease remains a challenge.
large-scale cancer sequencing efforts, including the Cancer Genome Atlas (TCGA) and the Clinical Proteome Tumor Analysis Consortium (CPTAC),Advancing the understanding of CRC at the genetic level, revealing frequent mutations and proposing several key pathways in the A- CRC phase, including cell cycle, glycolysis, etc. However, little is known about the first appearance of the mutation and its associated impact on CRC progression. In addition, genomic aberrations and their impact on proteomic alterations and phosphoproteomic roles in CRC carcinogenesis are not well understood. Based on the transcriptomics data set, the International Consortium and CPTAC have established four consensus molecular subtypes (CMSs, CMS1/2/3/4) and five intrinsic subtypes of CRC, providing deeper insights into the classification of CRC at A- CRC stages, respectively.However, CRC trajectories based on CMS and CRIS classifications have not been revealed.
Comparison of DEPs in different stages of CRC
In addition, both microsatellite instability (MSI) and stability (MSS) are present in solid tumors including CRC.However, the proteomic profile of MSI-and MSS-tumors of CRC has not been presented. According to the different location, CRC can be divided into left CRC(LCRC) and right CRC(RCRC), with different embryonic and anatomical characteristics, drug resistance and so on. The different characteristics of LCRC and RCRC progression remain unclear. Clinically, patients with bilateral tumor CRC (Mix group) had a poorer prognosis, with a greater prognosis than the LCRC monotherapy group and the RCRC monotherapy group.Given that the characteristics of the CRC Mix group are not well characterized, the underlying invasion mechanism has not been determined.
The study shows the proteomic patterns of 435 trace samples dissected from 148 CRC patients and paints a comprehensive proteomic picture of the entire process of CRC carcinogenesis.The study reveals the key transmission events in the progression of colorectal cancer, describes the different progression pathways of colorectal cancer based on CMS and CRIS subtype classification, expounds the characteristics of colorectal cancer patients based on MSI status, defines the characteristics of colorectal cancer sites, and proposes potential strategies to deal with colorectal cancer drug resistance.The study presents the first proteomic and genomic picture of colorectal cancer throughout its progression, greatly facilitating future basic and translational research into this deadly disease.
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