Using stage-matched genomic analysis to support molecular similarity of unknown-primary Merkel cell carcinoma and identify ARID1B as a prognostic marker.

Abstract

9584 Background: Merkel cell carcinoma (MCC) can present as nodal disease without an identifiable cutaneous primary, termed unknown-primary MCC (UP-MCC). UP-MCC has been reported to have distinct clinical outcomes compared with stage-matched known-primary MCC (KP-MCC), but its underlying biology is poorly understood. We compared the genomic landscapes of UP-MCC and stage IIIB KP-MCC and evaluated whether specific alterations are associated with survival in UP-MCC. Methods: A retrospective analysis was performed using the Dana-Farber Cancer Institute MCC repository (2012-2023). UP-MCC was defined as pathologically confirmed MCC without a detectable cutaneous primary; the comparator cohort comprised stage IIIB KP-MCC. Tumors underwent targeted next-generation sequencing (OncoPanel; 447 genes), and tumor mutational burden (TMB) and Merkel cell polyomavirus (MCPyV) status were recorded. Gene-level alteration frequencies were compared using Fisher’s exact test, and MCC-specific survival (MCCSS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards models. Results: Fifty-two patients were included (20 UP-MCC, 32 KP-MCC). UP-MCC and KP-MCC showed highly overlapping genomic landscapes, including similar distributions of MCPyV status, TMB, and recurrent driver alterations, with no gene-level differences detected. Within UP-MCC, SETBP1 alterations were associated with worse MCCSS (HR 6.74; 95% CI, 1.33–34.07; p=0.030), while ARID1B alterations identified a markedly high-risk UP-MCC subgroup with inferior MCCSS (HR 27.1; 95% CI, 3.02–243.11; p<0.001) and OS (HR 16.9; 95% CI, 1.9–152.9; p=0.004). All five ARID1B -altered UP-MCC patients died of MCC, compared with 4 of 15 ARID1B –wild-type; in multivariable analysis, ARID1B remained an independent predictor of worse MCCSS (p=0.003), whereas SETBP1 did not (p=0.313). In KP-MCC cohort, ARID1B was not significantly associated with MCCSS (p=0.1883). Conclusions: Stage-matched genomic profiling demonstrates molecular similarity between UP-MCC and KP-MCC, supporting the hypothesis that UP-MCC often represents regressed primary cutaneous tumors. Within UP-MCC, ARID1B alterations identify a high-risk subgroup with markedly inferior MCCSS, suggesting that targeted genomic profiling may refine risk stratification, surveillance strategies, and clinical trial design for patients with UP-MCC and these findings warrant validation in larger, multi-institutional cohorts. Baseline characteristics of UP-MCC and stage IIIB KP-MCC cohorts. Parameter UP-MCC (n=20) KP-MCC stage IIIB (n=32) p-value Age, mean (SD), years 68.2 (12.9) 74.2 (12.1) 0.204 Male sex, n (%) 13 (65.0) 26 (81.3) 0.323 MCPyV positive, n (%) 11 (55.0) 15 (46.9) 0.776 High TMB, n (%) 8 (40.0) 11 (34.4) 0.909 TMB, mean (SD), mut/Mb 14.1 (13.9) 18.7 (24.6) 0.572 SD= Standard Deviation.