(P 323) EVALUATION OF COSMIC MUTATIONAL SIGNATURES IN SOFT TISSUE SARCOMA

Objective: Previously in our study, the comprehensive genomic analysis of alterations in undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) tumors showed a significant number of genomic alterations, complex rearrangements and frequent genomic imbalances that affect the p53 and RB1-CDK4 pathways. Mutational signatures connect mutational patterns with biological and chemical processes that take place in cancers. Catalogue Of Somatic Mutations In Cancer (COSMIC) is a resource to explore the impact of these mutations on cancer development and progression. We aim to identify the mutational processes present in primary UPS/ MFS tumors, metastases, and tumor-derived cell lines using COSMIC’s mutational signature analysis. We aim to compare the mutational signatures in eight primary tumors to their matched tumor-derived cell lines that were established for use as in-vitro soft tissue sarcoma (STS) models and compare the mutation signatures of the seven primary tumors to the matched metastatic tumors to identify metastasis specific signatures.

Methods: Mutational signature analyses were performed to identify patterns of somatic base substitutions (SBS) in 45 primary UPS/MFS, 8 matched primary-cell line and 7 matched primary-metastatic tumors that aligned with the COSMIC mutational signatures.

Results: Using the COSMIC mutational signatures database, we found that SBS1 was the predominant signature in primary tumors (93%). SBS1 is associated with the endogenous mutational process initiated by spontaneous or enzymatic deamination of 5-methylcytosine to thymine, that results in C to T substitutions and other studies suggest it is related to the age of the individual. SBS3 was present in half of the primary tumors and is associated with the failure of double strand break repair.
Interestingly, SSB1 in cell line samples remained the dominant signature, however, the total number of signatures represented in the cell lines were more than the primary tumors. This suggests that cell lines were comprised of more diverse COSMIC mutational signatures and represent a sub-clonal population of tumor cells that persisted in-vitro.
Metastatic tumors also had SSB1 as the predominant signature, however overall, they had more signatures than their primary tumors, indicating changes in the underlying mutational processes during metastases.

Conclusion: A more comprehensive analysis of the COSMIC mutational signatures of our cohort can help elucidate tumor evolution, prognosis, and therapeutic strategies in STS.