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Review
. 2020 Jul;47(7):606-616.
doi: 10.1111/cup.13689. Epub 2020 May 11.

Germline mutations predisposing to melanoma

Atrin Toussi  1 , Nicole Mans  2 , Jeanna Welborn  2 , Maija Kiuru  1   3
Affiliations
Review

Germline mutations predisposing to melanoma

Atrin Toussi et al. J Cutan Pathol. 2020 Jul.

Abstract

Nearly 15% of melanomas occur in patients with a family history and a subset of these patients have a germline mutation in a melanoma predisposing gene. CDKN2A mutations are responsible for the majority of hereditary melanoma, but many other susceptibility genes have been discovered in recent years, including CDK4, TERT, ACD, TERF2IP, POT1, MITF, MC1R, and BAP1. Additionally, melanoma risk is increased in mixed cancer syndromes caused by mutations in PTEN, BRCA2, BRCA1, RB1, and TP53. While early onset, multiple tumors, and family cancer history remain the most valuable clinical clues for hereditary melanoma, characteristic epithelioid cytology of melanocytic tumors may suggest an underlying BAP1 mutation. Herein, we review the clinical and histopathologic characteristics of melanocytic tumors associated with these germline mutations and discuss the role of genetic counseling.

Keywords: CDKN2A; germline mutation; hereditary; melanocytic nevus; melanoma.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Melanoma associated with a germline deletion of exon 1B of CDKN2A gene. The patient had a history of multiple primary cutaneous melanomas and visceral metastases. A, Hemotoxylin and eosin (H&E), ×40. B, H&E, ×100. C, H&E, ×400
FIGURE 2
FIGURE 2
BAP1-inactivated nevus with epithelioid melanocytes. This adolescent patient had multiple BAP1-inctivated nevi. A, Hemotoxylin and eosin (H&E), ×40. B, H&E, ×100. C, H&E, ×400
FIGURE 3
FIGURE 3
Loss of nuclear BAP1 expression in a BAP1-inactivated melanocytoma. This tumor displays nuclear pleomorphism. A, Hemotoxylin and eosin (H&E), ×100. B, H&E, ×400. C, BAP1 immunohistochemistry, ×400. Large epithelioid tumor cells have lost BAP1 expression (arrow). Lymphocytes show normal nuclear expression of BAP1 (arrowhead)
FIGURE 4
FIGURE 4
Melanoma in situ in a patient with xeroderma pigmentosum. This 22-year old patient had a history of multiple melanomas (invasive and in situ) and numerous basal cell carcinomas. A, Hemotoxylin and eosin (H&E), ×40. B, H&E, ×100. C, H&E, ×400
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