Clinical and Immunologic Features of Germline Pathogenic Variant (gPV) Positive Patients with Melanoma

Abstract

Purpose: Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10-15% of all melanoma cases. No studies to date examine the immunologic features that may differentiate survival differences between germline pathogenic variant (gPV) positive patients with melanoma from gPV negative patients with melanoma. Experimental Design: Adult patients with melanoma and clinical characteristics suggesting hereditary predisposition to cancer were prospectively recruited to undergo germline testing and flow cytometric analysis of peripheral immune suppressor cells. Results: In this cohort, gPV positive patients (n=72) had a significantly improved melanoma specific survival (MSS) compared to gPV negative patients (n=411) [HRadj = .32, 95% CI (.13 - .82), p = .01]. These survival improvements amongst gPV positive patients were most apparent amongst cutaneous melanoma subtypes [HRadj = .12, 95% CI (.016 - .86), p = .03] and numerically improved in later stage (IIB-IV) patients [HRadj = .34, 95% CI (.10 – 1.11), p = .06]. Further, gPV positive patients had a significantly lower level of total circulating PMN-MDSCs compared to gPV negative patients (p = .01), which was most apparent in those diagnosed with later stages (IIB-IV) of melanoma (p = .009). Finally, a significant upregulation of inflammatory transcriptome signatures in later stage gPV positive patients (n=21) was observed in comparison to gPV negative patients (n=173) in the cutaneous melanoma cohort (SKCM) of The Cancer Genome Atlas (TCGA). Conclusions: gPV positive patients with melanoma exhibit improved MSS in addition to reduced peripheral PMN-MDSCs and an enhanced inflammatory microenvironment.