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

doi:10.1016/j.jdin.2023.01.013

. 2023 Jan 30:11:43-51.

doi: 10.1016/j.jdin.2023.01.013. eCollection 2023 Jun.

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 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.

PMID: 36876055
PMCID: PMC9978843
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

Alisa M Goldstein et al. JAAD Int. 2023.

. 2023 Jan 30:11:43-51.

doi: 10.1016/j.jdin.2023.01.013. eCollection 2023 Jun.

Authors

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.

PMID: 36876055
PMCID: PMC9978843
DOI: 10.1016/j.jdin.2023.01.013

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.

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Conflict of interest statement

None disclosed.

Figures

**Fig 1**
Cutaneous melanomas exhibiting spitzoid morphology from individuals with germline *POT1* variants. A, Low magnification (4.9×) of spitzoid subtype melanoma (case 14-B) from an individual with germline *POT1* p.Asp598Serfs∗22 variant. B, Higher magnification (25.3×) of case 14-B shows atypical melanocytes with abundant eosinophilic cytoplasm consistent with spitzoid morphology. C, Low magnification (2.9×) of spitzoid subtype melanoma (case 3) from an individual with germline *POT1* c.1164-1G>A splice acceptor variant. D, Higher magnification (21.1×) of case 3 shows epidermal and dermal nests of epithelioid and spindled melanocytes with abundant cytoplasm; some junctional nests show separation from the surrounding epidermis (*arrows*), which is a feature of Spitz tumors. E, Low magnification (3.7×) of a melanoma (case 9) from an individual with germline *POT1* p.Lys427Arg variant; the tumor exhibits areas of spitzoid (*outlined in red*) and nonspitzoid differentiation. F, Higher magnification (40×) photomicrograph of spitzoid area in case 9 showing enlarged epithelioid melanocytes with abundant eosinophilic cytoplasm. G, Higher magnification (40×) photomicrograph of nonspitzoid area in case 9 showing epithelioid and spindled melanocytes that lack abundant cytoplasm.

**Fig 2**
Cutaneous melanoma exhibiting spitzoid morphology with acantholytic features from individual with germline *POT1* variant. Case 6 is from an individual with a germline *POT1* variant (p.Arg117His) and pathology shows a sheet-like proliferation of spitzoid cells with loss of cohesion, consistent with an acantholytic growth pattern.

**Fig 3**
Cutaneous melanoma exhibiting spitzoid morphology in the dermis from individual with germline *POT1* variant. A, Case 1 is from an individual with a germline variant in *POT1* (p.Arg137His) and pathology shows a superficial spreading growth pattern (nesting, pagetoid scatter, and increased pigmentation) in the epidermis and an invasive component with spitzoid morphology (*asterisk*). B, Higher magnification (40×) of spitzoid area in case 1.

**Fig 4**
Cutaneous melanomas exhibiting spitzoid morphology from individuals with *TERT*, *TERF2IP*, and *ACD* variants. A, Case 24 is from an individual with a germline variant in *TERT* (p.Ala202Thr) and pathology shows nests and sheets of large epithelioid melanocytes with abundant eosinophilic cytoplasm consistent with spitzoid morphology (40× magnification). B, Case 18 is from an individual with a germline variant in *TERF2IP* (p.Glu304del) and pathology shows nests and single cells of melanocytes with abundant eosinophilic cytoplasm in the papillary dermis consistent with spitzoid morphology (40× magnification). C, Case 20-A is from an individual with a germline variant in *TERF2IP* (p.Pro285Ser) and pathology shows a compound melanocytic lesion with epidermal and dermal nests of epithelioid melanocytes with abundant eosinophilic cytoplasm consistent with spitzoid morphology (40× magnification). D, Case 21-C is from an individual with a germline variant in *ACD* (p.Val432Ala) and pathology shows epidermal and dermal nests of melanocytes with abundant eosinophilic cytoplasm, consistent with spitzoid morphology, and a dense lymphocytic infiltrate (40× magnification).

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References

1. Potrony M., Badenas C., Aguilera P., et al. Update in genetic susceptibility in melanoma. Ann Transl Med. 2015;3(15):210. doi: 10.3978/j.issn.2305-5839.2015.08.11. - DOI - PMC - PubMed
1. Goldstein A.M., Chan M., Harland M., et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007;44(2):99–106. doi: 10.1136/jmg.2006.043802. - DOI - PMC - PubMed
1. Shi J., Yang X.R., Ballew B., et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet. 2014;46(5):482–486. doi: 10.1038/ng.2941. - DOI - PMC - PubMed
1. Robles-Espinoza C.D., Harland M., Ramsay A.J., et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014;46(5):478–481. doi: 10.1038/ng.2947. - DOI - PMC - PubMed
1. Aoude L.G., Pritchard A.L., Robles-Espinoza C.D., et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst. 2015;107(2) doi: 10.1093/jnci/dju408. - DOI - PMC - PubMed

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[1] Potrony M., Badenas C., Aguilera P., et al. Update in genetic susceptibility in melanoma. Ann Transl Med. 2015;3(15):210. doi: 10.3978/j.issn.2305-5839.2015.08.11. - DOI - PMC - PubMed

[2] Potrony M., Badenas C., Aguilera P., et al. Update in genetic susceptibility in melanoma. Ann Transl Med. 2015;3(15):210. doi: 10.3978/j.issn.2305-5839.2015.08.11. - DOI - PMC - PubMed

[3] Goldstein A.M., Chan M., Harland M., et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007;44(2):99–106. doi: 10.1136/jmg.2006.043802. - DOI - PMC - PubMed

[4] Goldstein A.M., Chan M., Harland M., et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007;44(2):99–106. doi: 10.1136/jmg.2006.043802. - DOI - PMC - PubMed

[5] Shi J., Yang X.R., Ballew B., et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet. 2014;46(5):482–486. doi: 10.1038/ng.2941. - DOI - PMC - PubMed

[6] Shi J., Yang X.R., Ballew B., et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet. 2014;46(5):482–486. doi: 10.1038/ng.2941. - DOI - PMC - PubMed

[7] Robles-Espinoza C.D., Harland M., Ramsay A.J., et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014;46(5):478–481. doi: 10.1038/ng.2947. - DOI - PMC - PubMed

[8] Robles-Espinoza C.D., Harland M., Ramsay A.J., et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014;46(5):478–481. doi: 10.1038/ng.2947. - DOI - PMC - PubMed

[9] Aoude L.G., Pritchard A.L., Robles-Espinoza C.D., et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst. 2015;107(2) doi: 10.1093/jnci/dju408. - DOI - PMC - PubMed

[10] Aoude L.G., Pritchard A.L., Robles-Espinoza C.D., et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst. 2015;107(2) doi: 10.1093/jnci/dju408. - DOI - PMC - PubMed

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

Affiliations

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

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