Elevated non-coding promoter mutations are associated with malignant transformation of melanocytic naevi to melanoma

Andrew J Colebatch; Elizabeth C Paver; Ismael A Vergara; John F Thompson; Georgina V Long; James S Wilmott; Richard A Scolyer

doi:10.1016/j.pathol.2021.12.289

Elevated non-coding promoter mutations are associated with malignant transformation of melanocytic naevi to melanoma

Pathology. 2022 Aug;54(5):533-540. doi: 10.1016/j.pathol.2021.12.289. Epub 2022 Mar 2.

Authors

Andrew J Colebatch¹, Elizabeth C Paver¹, Ismael A Vergara², John F Thompson³, Georgina V Long⁴, James S Wilmott², Richard A Scolyer⁵

Affiliations

¹ Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
² Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
³ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
⁴ Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, St Leonards, NSW, Australia.
⁵ Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Electronic address: richard.scolyer@health.nsw.gov.au.

PMID: 35248370
DOI: 10.1016/j.pathol.2021.12.289

Abstract

Evolution from a benign naevus to a melanoma results principally from the stepwise accumulation of mutations. We used a custom next generation sequencing (NGS) panel targeting specific melanoma associated genes to analyse and compare differences between melanomas and their precursor naevi in coding and non-coding mutations and copy number aberrations, with a view to implementing this technique as an ancillary test to assist in the interpretation of difficult to diagnose melanocytic tumours. Fifteen cases of cutaneous melanoma with an adjacent morphologically benign (presumed precursor) naevus were selected. A custom NGS panel was used to sequence 54 melanoma associated genes in both the melanoma and the associated naevus for each case. In three cases, two morphologically distinct regions of the melanoma were sequenced. The adjacent (non-lesional) skin was also tested in nine cases. One case was excluded following molecular testing and clinicopathological reclassification as an epidermotropic melanoma metastasis. Twelve of the 14 tumours showed either BRAF or NRAS driver mutations. The melanomas harboured significantly more mutations than the adjacent naevi, particularly in non-coding promoter regions (p=0.002). There were significantly more non-coding promotor mutations in NRAS-mutant melanomas than BRAF-mutant melanomas (p=0.004). Mutations in TERT promoter regions were found preferentially in melanomas. Oncogenic events found exclusively in melanomas included PTEN loss in two BRAF-mutant melanomas and RAC1 P29S hyperactivating mutations in two NRAS-mutant melanomas. Higher numbers of mutations were present in melanomas compared to their precursor naevi. These findings support the further evaluation of this melanoma custom NGS panel as an ancillary test for interpreting difficult borderline melanocytic lesions.

Keywords: BRAF; NRAS; diagnosis; melanoma; mutation; naevus; nevus; next generation sequencing; pathology.

MeSH terms

Cell Transformation, Neoplastic / genetics
Humans
Melanoma* / diagnosis
Melanoma* / genetics
Melanoma* / pathology
Mutation
Nevus, Epithelioid and Spindle Cell* / genetics
Nevus, Pigmented* / diagnosis
Nevus, Pigmented* / genetics
Nevus, Pigmented* / pathology
Promoter Regions, Genetic
Proto-Oncogene Proteins B-raf / genetics
Skin Neoplasms* / diagnosis
Skin Neoplasms* / genetics
Skin Neoplasms* / pathology

Substances

Proto-Oncogene Proteins B-raf