148P Mic60 loss as a driver of aggressive breast cancer phenotype

Background: Sarcomas are molecularly heterogeneous malignancies with limited targeted therapeutic options.Deletions in the 9p21 locus-encompassing MTAP, CDKN2A and CDKN2B-are increasingly recognised as biologically aggressive events and have emerged as actionable vulnerabilities through synthetic-lethal targeting of the PRMT5/MAT2A axis.We aimed to characterise the prevalence and distribution of MTAP and CDKN2A/B losses across a real-world, histologically diverse sarcoma cohort. Methods:We retrospectively analysed next-generation sequencing results from sarcoma samples profiled between December 2022 and December 2025 at Hospital Clnico San Carlos.Tumour classifications were harmonised according to WHO 2020 criteria.Genomic profiling was performed using FoundationOne Heme, assessing single-nucleotide variants, copy-number alterations and fusion events.MTAP and CDKN2A/B deletions were reported as homozygous losses.Results: A total of 57 sarcoma samples underwent NGS profiling (46 soft-tissue sarcomas STS, 6 bone sarcomas, 4 GIST, and 1 other rare subtype).CDKN2A/B loss was identified in 7 patients (12%), predominantly in STS (6/46; 13%), followed by bone sarcomas (1/6; 17%).No CDKN2A/B deletions were detected in GIST or other tumour types.Co-deletion of MTAP and CDKN2A/B occurred in 2 patients (4%), both within the STS subgroup, consistent with the expected pattern of coordinated 9p21 loss.No MTAP co-deletions were observed in bone sarcomas, GIST or other subtypes.Conclusions: MTAP loss with concurrent CDKN2A/B deletion is a recurrent crosshistology event in aggressive sarcoma subtypes and represents a promising biomarker for synthetic-lethal PRMT5/MAT2A-targeted strategies.These findings support the systematic molecular profiling of sarcomas and the prioritisation of patients with 9p21-deleted tumours for enrolment in early-phase clinical trials exploring this therapeutic strategy.