Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series

Alisa M Goldstein; Richard Qin; Emily Y Chu; David E Elder; Daniela Massi; David J Adams; Paul W Harms; Carla Daniela Robles-Espinoza; Julia A Newton-Bishop; D Timothy Bishop; Mark Harland; Elizabeth A Holland; Anne E Cust; Helen Schmid; Graham J Mann; Susana Puig; Miriam Potrony; Llucia Alos; Eduardo Nagore; David Millán-Esteban; Nicholas K Hayward; Natasa Broit; Jane M Palmer; Vaishnavi Nathan; Elizabeth G Berry; Esteban Astiazaran-Symonds; Xiaohong R Yang; Margaret A Tucker; Maria Teresa Landi; Ruth M Pfeiffer; Michael R Sargen

doi:10.1016/j.jdin.2023.01.013

Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series

JAAD Int. 2023 Jan 30:11:43-51. doi: 10.1016/j.jdin.2023.01.013. eCollection 2023 Jun.

Authors

Alisa M Goldstein¹, Richard Qin¹, Emily Y Chu², David E Elder³, Daniela Massi⁴, David J Adams⁵, Paul W Harms⁶, Carla Daniela Robles-Espinoza^{5

7}, Julia A Newton-Bishop⁸, D Timothy Bishop⁸, Mark Harland⁸, Elizabeth A Holland^{9

10}, Anne E Cust^{9

11

12}, Helen Schmid^{9

10

12}, Graham J Mann^{10

12

13}, Susana Puig^{14

15}, Miriam Potrony^{15

16}, Llucia Alos¹⁷, Eduardo Nagore^{18

19}, David Millán-Esteban^{18

19}, Nicholas K Hayward²⁰, Natasa Broit²⁰, Jane M Palmer²⁰, Vaishnavi Nathan²⁰, Elizabeth G Berry²¹, Esteban Astiazaran-Symonds¹, Xiaohong R Yang¹, Margaret A Tucker¹, Maria Teresa Landi¹, Ruth M Pfeiffer¹, Michael R Sargen^{1

22}

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
² Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
³ Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
⁴ Section of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy.
⁵ Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, England.
⁶ Department of Pathology, University of Michigan, Ann Arbor, Michigan.
⁷ Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Campus Juriquilla, Santiago de Querétaro, Qro, Mexico.
⁸ Division of Haematology and Immunology, Institute of Medical Research at St James's, University of Leeds, Leeds, England.
⁹ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council, NSW, Sydney, Australia.
¹⁰ Centre for Cancer Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia.
¹¹ Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia.
¹² Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.
¹³ John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
¹⁴ Melanoma Unit, Department of Dermatology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona University, Barcelona, Spain.
¹⁵ Centre of Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain.
¹⁶ Melanoma Unit, Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona University, Barcelona, Spain.
¹⁷ Pathology Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain.
¹⁸ Department of Dermatology, Fundación Instituto Valenciano de Oncología, València, Spain.
¹⁹ School of Medicine, Universidad Católica de València San Vicente Mártir, València, Spain.
²⁰ QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
²¹ Department of Dermatology, Oregon Health and Science University, Portland, Oregon.
²² Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Abstract

Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.

Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology.

Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist.

Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology.

Limitations: Findings may not be generalizable to nonfamilial melanoma cases.

Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.

Keywords: ACD; CI, confidence interval; GPV, germline pathogenic variant; OR, odds ratio; POT1; TERF2IP; TERT; TMG, telomere maintenance gene; familial melanoma; melanoma; spitz melanoma; spitzoid melanoma.

Grants and funding

MR/V000292/1/MRC_/Medical Research Council/United Kingdom