EACR25-0971

Different mutational patterns in primary colorectal cancer and its paired synchronous or metachronous metastasis and their association with patient outcomes

M. Rajtmajerova1, F. Ambrozkiewicz1, V. Hlavac2, A. Trailin1, L. Cervenkova1, J. Bruha3, P. Soucek2, S. Susova2, V. Liska3, K. Hemminki1
1Charles University, Faculty of Medicine In Pilsen, Biomedical Center, Pilsen, Czech Republic
2National Institute of Public Health, Toxicogenomics Unit, Prague, Czech Republic
3Charles University, Faculty of Medicine In Pilsen, Department of Surgery, Pilsen, Czech Republic
Introduction:

Colorectal Cancer (CRC) is the second most deadly cancerous disease worldwide. Early diagnosis is vital for successful treatment as survival gradually drops from 90 % at stage I below 20% for stage IV. Most frequently CRC metastasizes to the liver, and it can be diagnosed simultaneously with primary tumor (synchronous metastasis) or after primary tumor (pCRC) removal (metachronous metastasis). We performed whole exome sequencing to depict genetic changes in primary tumors and their paired synchronous or metachronous liver metastases.

Material and method:

Whole exome sequencing was performed on 87 samples of pCRC and its paired liver metastasis (LM) and 36 singletons (where only one tissue type was available). Firstly, we examined differential mutated genes and type of mutations and CNV. Secondly, we focused on the tumor mutation burden (TMB) in pCRC and LM. We evaluated its association with overall survival (OS) and disease-free survival (DFS) from colon and liver surgery by Cox regression and Kaplan-Meier method. For all analysis, different chronicity of metastases was considered.

Result and discussion:

APC and TP53 were identified as the most commonly mutated genes in pCRC (both ~50%) and its metachronous metastasis (both 64%). For synchronous metastasis we observed much lower frequencies of mutations in APC gene (40%). MPDZ gene mutations were characteristic to metachronous pCRC only, mutations in VCAN, MTCL1, MDN1, SHROOM2, SPEG and GLI2 were more prevalent in synchronous pCRC. FBN1 mutations were unique to synchronous LM. We observed significantly higher TMB (p=0.03) in metachronous group when comparing pCRC and LM. On the other hand, in the synchronous group, we observed a significant positive correlation between TMB in pCRC and LM. We observed longer OS (HR=0.3, p=0.01) for patients with higher TMB in pCRC leading to synchronous metastasis. On the other hand, higher TMB in Metachronous metastasis was associated with shorter DFS (HR=2.01, p=0.03).

Conclusion:

The results suggest that distinct tumor progression pathways account for different chronicity and may have ultimate impact on patient’s prognosis.