Genomic copy number burden distinguishes the diagnosis and prognosis of primary dermal melanoma

Zhao, P; Chew, C; Szeto, P; Berry, W; Photiou, L; Wong, NC; Dinan, A; McLean, CA; Marshall, VM; Cheung, J; Adler, NR; Goodarzy, F; Andrews, MC; Mar, VJ; Papenfuss, AT; Shackleton, M

Author(s): Zhao, P; Chew, C; Szeto, P; Berry, W; Photiou, L; Wong, NC; Dinan, A; McLean, CA; Marshall, VM; Cheung, J; Adler, NR; Goodarzy, F; Andrews, MC; Mar, VJ; Papenfuss, AT; Shackleton, M;
Details: Publication Year 2026-04-17,Volume 194,Issue #5,Page 899-913
Journal Title: British Journal of Dermatology
Abstract: BACKGROUND: Primary dermal melanoma (PDM) is a subtype of melanoma with histological features indiscernible from nonepidermal metastatic cutaneous melanoma deposits, although patients with PDMs have more favourable outcomes than patients with dermal metastases. Despite the histological similarity, it is not known whether the mutational landscapes of PDMs and dermal metastases are also similar, or whether distinct mutational patterns might exist in PDMs. OBJECTIVES: To identify genomic features that distinguish PDMs from nonepidermal cutaneous melanoma metastases, thereby enhancing the accuracy of clinical diagnosis and prognostication. METHODS: Twenty PDMs and 23 nonepidermal cutaneous metastases were sequenced using the TSO500 panel. Genomic features distinguishing PDMs and metastases were identified using the regularized random forest model and feature engineering. Predictive biomarkers of patient event-free survival were identified using Lasso-Cox regression. RESULTS: PDMs and nonepidermal cutaneous metastases harboured point mutations characteristic of melanomas of epidermal origin. Compared with PDMs, metastases exhibited distinct copy number variations (CNVs) that led to gains of oncogenes and losses of tumour suppressor genes. Extreme focal amplifications were uniquely identified in cases of nonepidermal cutaneous metastases but were absent in PDMs. Large-scale CNVs and focal amplifications were identified as discriminative biomarkers between PDMs and metastases. A clinical diagnosis of PDM and an absence of BRAF CNVs collectively were associated with a reduced risk of death or disease progression after surgery vs. a clinical diagnosis of metastasis or of PDM with BRAF CNVs. CONCLUSION: We found that CNVs were the strongest discriminative features between PDMs and nonepidermal cutaneous metastases, with large-scale and focal CNVs abundant in metastases but not in PDMs. Notably, integrating BRAF copy number analysis with standard clinical criteria for diagnosing PDMs improved risk stratification after surgery. These data highlight the ability of panel-based genomic sequencing that enables the detection of CNVs to inform the clinical management of melanoma.; Melanoma is the deadliest type of skin cancer. Most often, melanoma starts in the top layer of skin, called the 'epidermis'. These melanomas can 'metastasize'. This means they can spread to deeper skin layers and other places in the body. When melanoma metastasizes, people have poorer outcomes. There is a less common subtype of melanoma, known as 'primary dermal melanoma' (or 'PDM' for short). This begins in the dermis, which is the layer of skin below the epidermis. This type of melanoma looks very similar to metastasized melanoma but is less dangerous. This makes it difficult for doctors to make a correct diagnosis and decide how likely people are to have a relapse in their cancer. So, we need to be able to distinguish PDM from metastasized melanoma. To address this, we analysed DNA from 20 PDMs and 23 metastases from a group of Australian people. We found that changes in DNA called 'copy number variations' can tell PDMs and metastases apart. Copy number variation is a type of genetic difference where people have different numbers of copies of a gene. Copy number variations were far more common in dermal metastases than in PDMs. We also found that copy number variations affecting a gene called 'BRAF' were linked to patient outcomes. People who had PDMs without copy number variations in BRAF surgically removed were unlikely to have a relapse in their cancer. But, relapses were more common in people who had metastases removed or who had PDMs affected by copy number variations in the BRAF gene removed. Our findings suggest that analysing copy number variation improves the ability of doctors to diagnose and predict relapse in people with dermal melanomas. This could change the way that patients are cared for after surgical removal of these melanomas.; eng
Publisher: Oxford Academic
Keywords: Humans; *Melanoma/genetics/diagnosis/mortality/secondary; *Skin Neoplasms/genetics/diagnosis/mortality/pathology; *DNA Copy Number Variations/genetics; Prognosis; Male; Female; Middle Aged; Aged; Biomarkers, Tumor/genetics; Adult; Point Mutation; Diagnosis, Differential; Aged, 80 and over; Proto-Oncogene Proteins B-raf/genetics; Cutaneous Malignant Melanoma
Research Division(s): Bioinformatics and Computational Biology
PubMed ID: 41364704
Publisher's Version: https://doi.org/10.1093/bjd/ljaf507
Open Access at Publisher's Site: https://doi.org/10.1093/bjd/ljaf507
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-04-27 03:52:48

Last Modified: 2026-04-30 10:18:57