Background: Although surgical resection generally yields excellent outcomes, a number
of patients with colon cancer still have relapse or metastasis after surgery. Adjuvant chemotherapy
in tumor stage III has been demonstrated to eradicate micrometastasis and improve survival, whereas
the benefits of adjuvant chemotherapy in tumor stage II remain controversial. The leading cause
is the lack of understanding of the molecular basis of underlying metastatic mechanisms.
Objective: This study aimed to identify molecular subtype(s) of colon cancer with a high risk of
metastasis and provide potential biomarkers for prognostic prediction in tumor stage II.
Methods: Based on the assumption that colon cancer evolves because of the stepwise accumulation
of a series of genetic mutations, we performed a systematic investigation on the molecular basis of
colon cancer through applying restart random walk on the PPI network. To compare functional similarity
of patients, we extracted mutation-propagating modules of each patient and calculated their
enrichment score in 50 hallmark gene sets. According to functional similarity matrix, we classified
colon cancers with positive lymphovascular invasion and the prognosis of molecular subtypes. We
determined the molecular characteristics of subtypes by enrichment analysis of subtype-specific
genetic mutations. Additionally, we identified potential biomarkers for predicting patients with a
high risk of metastasis in stage II through differential analysis of miRNA expression profiles of
subtypes. Then we used two independent data sets to construct a random forest classifier and performed
10-fold cross-validation of miRNA biomarkers.
Results: Firstly, we identified two molecular subtypes of colon cancer with positive lymphovascular
invasion as well as their associated biological characteristics: LVI1=Canonical subtype (110,
85%); LVI2=Metastatic subtype (20, 15%). Secondly, we identified 11 miRNA biomarkers for predicting
patients with a high risk of metastasis in tumor stage II.
Conclusion: Our findings put forward a detailed classification for colon cancer and provided risk
biomarkers for stage II patients to determine whether to take adjuvant chemotherapy after surgery.