Abstract
Purpose: Malignant melanoma represents the most lethal skin cancer with germline predispositions thought to comprise 10% to 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 ¼ 72) had a significantly improved melanoma-specific survival (MSS) compared with gPV-negative patients (n ¼ 411; HRadj, 0.32; 95% CI, 0.13–0.82; P ¼ 0.01). These survival improvements among gPV-positive patients were most apparent among cutaneous melanoma subtypes (HRadj, 0.12; 95% CI, 0.016–0.86; P ¼ 0.03) and numerically improved in later-stage (IIB–IV) patients (HRadj, 0.34; 95% CI, 0.10–1.11; P ¼ 0.06). Further, gPV-positive patients had a significantly lower level of total circulating PMN-MDSC compared with gPV-negative patients (P ¼ 0.01), which was most apparent in those diagnosed with later stages (IIB–IV) of melanoma (P ¼ 0.009). Finally, a significant upregulation of inflammatory transcriptome signatures in later-stage gPV-positive patients (n ¼ 21) was observed in comparison with gPV-negative patients (n ¼ 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-MDSC and an enhanced inflammatory microenvironment.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 564-574 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 30 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 1 2024 |
Funding
The authors would like to thank the Gross Family Melanoma Registry and the Gross Family for providing funding for this project. We also greatly appreciate the patients of Cleveland Clinic and their families for allowing us to utilize their medical information to help improve care. We would also like to acknowledge Dr. Sujata Patil of Cleveland Clinic Quantitative Health Sciences (QHS) for her statistical input. We are grateful to the researchers of the TCGA Research Network for providing the wealth of resources that has been generated by the TCGA Research Network (https://www.cancer.gov/tcga). J. Arbesman reports personal fees from Association of Community Cancer Centers and grants from Castle Biosciences and Variant Bio outside the submitted work. P. Funchain reports grants from Pfizer and Taiho Oncology; grants and personal fees from BMS; personal fees from Merck, GigaGen, Eisai, Novartis, Array, and Hexal AG; and other support from Nirvana Healthcare Ventures outside the submitted work. No disclosures were reported by the other authors.
ASJC Scopus subject areas
- General Medicine
