Amino acid metabolism-based molecular classification of colon adenocarcinoma via in silico analysis

Abstract

Amino acid metabolism is closely related to the occurrence and development of colon adenocarcinoma (COAD). Studies on the relationship between COAD and the expression of amino acid metabolism are still rare. Based on in silico analysis, we used 358 amino acid metabolism-related genes (AAMRGs) to determine the amino acid metabolism characteristics and then classified COAD into two distinct subtypes, namely AA1 and AA2. Then we analyzed the clinical characteristics, somatic mutation landscape, transcriptome profile, metabolism signatures, immune infiltration, and therapy sensitivity of these two subtypes. The AA1 subtype had inferior overall survival and was characterized by lower amino acid metabolic activity, higher tumor mutation burden, and higher immune cell infiltration, while AA2 displayed higher metabolic activity and relatively better survival. Furthermore, the AA1 subtype was likely to benefit from irinotecan in chemotherapy and immune checkpoint blockade therapy including programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) immune checkpoint inhibitor but was resistant to targeted therapy cetuximab. The AA2 subtype showed higher sensitivity to 5-fluorouracil and oxaliplatin. To provide perspectives on cell-specific metabolism for further investigation, we explored metabolic activity in different cell types including lymphocytes, mast cells, myeloid cells stromal cells, and epithelial cells via colorectal cancer single-cell data. Additionally, to assist in clinical decision-making and prognosis prediction, a 60-AAMRG-based classifier was generated and validated in an independent cohort.

Keywords: amino acid metabolism; classification; colon adenocarcinoma; immune signature; prognosis; therapy.