Proteomic profiling of colorectal adenomas identifies a predictive risk signature for development of metachronous advanced colorectal neoplasia.

BACKGROUND & AIMS: Colonic adenomatous polyps, or adenomas, are frequent precancerous lesions and the origin of most cases of colorectal adenocarcinoma. However, we know from epidemiological studies that although most colorectal cancers originate from adenomas, only a small fraction of adenomas (3-5%) ever progress to cancer. At present, there are no molecular markers to guide follow-up surveillance programs.

METHODS: We profiled by mass spectrometry (MS)-based proteomics combined with machine learning analysis a selected cohort of formalin fixed paraffin embedded HG adenomas with long clinical follow-up, collected as part of the Danish national screening program. We grouped subjects in the cohort according to their subsequent history of findings: a non-metachronous advanced neoplasia group (G0), with no new HG adenomas or CRC up to 10 years after polypectomy, and a metachronous advanced neoplasia group (G1) where individuals developed a new HG adenoma or CRC within five years of diagnosis.

RESULTS: We generated a proteome dataset from 98 selected HG adenoma samples, including 20 technical replicates, of which 45 samples belonged to the non-metachronous advanced neoplasia group and 53 to the metachronous advanced neoplasia group. The clear distinction of these two groups seen in an UMAP plot indicated that the information contained within the abundance of the ∼5,000 proteins was sufficient to predict future occurrence of HG adenomas or development of CRC.

CONCLUSIONS: We performed an in-depth analysis of quantitative proteomic data from 98 resected adenoma samples using various novel algorithms and statistical packages, and found that their proteome can predict development of metachronous advanced lesions and progression several years in advance.