Proteomic characteristics reveal the signatures and the risks of T1 colorectal cancer metastasis to lymph nodes
- Fudan University, China
- National Center for Protein Sciences, China
Abstract
The presence of lymph node metastasis (LNM) affects treatment strategy decisions in T1NxM0 colorectal cancer (CRC), but the currently used clinicopathological-based risk stratification cannot predict LNM accurately. In this study, we detected proteins in formalin-fixed paraffin-embedded (FFPE) tumor samples from 143 LNM-negative and 78 LNM-positive patients with T1 CRC and revealed changes in molecular and biological pathways by label-free liquid chromatography tandem mass spectrometry (LC-MS/MS) and established classifiers for predicting LNM in T1 CRC. An effective 55-proteins prediction model was built by machine learning and validated in a training cohort (N=132) and two validation cohorts (VC1, N=42; VC2, N=47), achieved an impressive AUC of 1.00 in the training cohort, 0.96 in VC1 and 0.93 in VC2, respectively. We further built a simplified classifier with 9 proteins, and achieved an AUC of 0.824. The simplified classifier was performed excellent in two external validation cohorts. The expression patterns of 13 proteins were confirmed by immunohistochemistry, and the IHC score of 5 proteins were used to build a IHC predict model with an AUC of 0.825. RHOT2 silence significantly enhanced migration and invasion of colon cancer cells. Our study explored the mechanism of metastasis in T1 CRC and can be used to facilitate the individualized prediction of LNM in patients with T1 CRC, which may provide a guidance for clinical practice in T1 CRC.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures. The proteome raw data that support the findings of this study have been deposited to the ProteomeXchange Consortium (dataset identifier: PXD041476, https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041476) via the iProX partner repository (https://www.iprox.cn/) under Project ID IPX0003019000 at https://www.iprox.cn/page/project.html?id=IPX0003019000.
Article and author information
Author details
Funding
National Key Research and Development Program of China
- Chen Ding
Clinical Research Plan of SHDC
- Jianming Xu
Program of Shanghai Academic Research Leader
- Chen Ding
Shuguang Program og Shanghai Education Development Foundation and Shanghai Municipal Education Commission
- Chen Ding
National Natural Science Foundation of China
- Chen Ding
the Major Project of Special Development Funds of Zhangjiang National Independent Innovation Demonstration Zone
- Chen Ding
Shanghai Municipal Science and Technology Major Project
- Chen Ding
the Fudan original research personalized support project
- Chen Ding
CAMS Innovation Fund for Medical Sciences
- Fuchu He
Shanghai Science and Technology Committee Project
- Jianming Xu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Aparna Parikh
Ethics
Human subjects: The present study was carried out comply with the ethical standards of Helsinki Declaration II and approved by the Institution Review Board of Fudan University Zhongshan Hospital (B2019-166).
Version history
- Received: August 24, 2022
- Preprint posted: September 23, 2022 (view preprint)
- Accepted: May 5, 2023
- Accepted Manuscript published: May 9, 2023 (version 1)
- Version of Record published: June 1, 2023 (version 2)
Copyright
© 2023, Zhuang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Proteomic characteristics reveal the signatures and the risks of T1 colorectal cancer metastasis to lymph nodes
eLife 12:e82959.
https://doi.org/10.7554/eLife.82959
Further reading
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- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
