Molecular profile of metastatic colon cancer

1Research Institute of Oncology, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk

2Federal State Budgetary Educational Institution of Higher Education “Siberian State Medical University” of the Ministry of Health of the Russian Federation, Tomsk

Introduction. Metastatic colon cancer (mCC) is plicates its prognosis and the choice of an effective a heterogeneous disease, which significantly com- treatment strategy for patients. The use of mСС mo-10 | Cardiometry | Issue 29. November 2023

lecular profiling data will allow identifying an optimal approach to justify the choice of therapy and increase the patient’s survival rates.

Aim . Our aim was to assess the molecular subtypes of the primary CC tumors and liver metastases based on the transcriptomic analysis.

Materials and methods . The study included samples of tumor and adjacent normal tissue of the colon, as well as metastatic nodules to the liver, obtained from two patients before the stage of their antitumor treatment. Using the PureLink RNA Mini Kit (Invit-rogen, USA), RNA was isolated from biopsy samples. Sequencing libraries were prepared using the KAPA RNA HyperPrep Kit with RiboErase (HMR) (KAPA, South Africa). Whole-transcriptome sequencing was performed with the NextSeq500 system (Illumina, USA).

Results. Our analysis of the studied transcripts of colon tumor tissue using the Phantasus web tool showed the top 20 overexpressed genes: WNT5A, FENDRR, DES, SELENOM, APLN, DMBT1, SNHG3, TSPAN11, MUC1, PCSK1, RPS29, C1QBP, MFSD4A, LEFTY1, NOS2, COL9A1, PDPN, FZD8, TNFRSF11A and CDCA4. The signaling cascades most enriched in the colon tumor tissue were identified: c-Myc, RB/ E2F, mTOR, Hedgehog, and oxidative phosphorylation pathways were recognized. Thus, the studied samples of the colon tumor tissue are potentially associated with the canonical molecular subtype of CC (CMS2), which, according to the reference literature, is characterized by activation of the Wnt and c-MYC signaling cascades, a microsatellite-related stable phenotype (MSS), as well as high chromosomal instability (CIN). In the metastatic liver nodules, overexpression of the top 20 genes was detected: ALB, APOA1, FGG, ITIH3, CYP2A6, GC, SERPINC1, CRP, ADH1A, CY-P4A11, C8B, ORM2, F11, ACSM5, SERPIND1, HP, FGA, TF, AMBP, P.L.G. A detailed analysis of the signaling cascades showed a high enrichment in those samples of metabolic pathways with xenobiotics and steroids, as well as the cascades of the complement system and the intracellular pathways regulating the coagulation process. Thus, functional annotation of the transcripts of metastatic nodules in the liver allows us to assign them to the molecular subtype CMS3, which is associated with dysregulation of metabolic processes, a heterogeneous MSI phenotype, a low level of CIN and a high occurrence rate of KRAS gene mutations.

Conclusions . Fundamental differences have been established in the molecular genetic profile of colon carcinomas and the associated liver metastases. Our analysis of the transcriptome of the colon tumor tissue allows us to classify them as the molecular subtype CMS2; the transcripts of the metastatic nodules in the liver potentially correspond to the CMS3 variant.