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

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-EstebanNicholas 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

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	43-51
Number of pages	9
Journal	JAAD International
Volume	11
DOIs	https://doi.org/10.1016/j.jdin.2023.01.013
State	Published - Jun 2023

Keywords

ACD
POT1
TERF2IP
TERT
familial melanoma
melanoma
spitz melanoma
spitzoid melanoma

ASJC Scopus subject areas

Dermatology

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10.1016/j.jdin.2023.01.013

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Goldstein, A. M., Qin, R., Chu, E. Y., Elder, D. E., Massi, D., Adams, D. J., Harms, P. W., Robles-Espinoza, C. D., Newton-Bishop, J. A., Bishop, D. T., Harland, M., Holland, E. A., Cust, A. E., Schmid, H., Mann, G. J., Puig, S., Potrony, M., Alos, L., Nagore, E., ... Sargen, M. R. (2023). 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 International, 11, 43-51. https://doi.org/10.1016/j.jdin.2023.01.013

Goldstein, AM, Qin, R, Chu, EY, Elder, DE, Massi, D, Adams, DJ, Harms, PW, Robles-Espinoza, CD, Newton-Bishop, JA, Bishop, DT, Harland, M, Holland, EA, Cust, AE, Schmid, H, Mann, GJ, Puig, S, Potrony, M, Alos, L, Nagore, E, Millán-Esteban, D, Hayward, NK, Broit, N, Palmer, JM, Nathan, V, Berry, EG, Astiazaran-Symonds, E, Yang, XR, Tucker, MA, Landi, MT, Pfeiffer, RM & Sargen, MR 2023, '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 International, vol. 11, pp. 43-51. https://doi.org/10.1016/j.jdin.2023.01.013

@article{7104073102954dabb2bc5ec466b8c92e,

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

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, POT1, TERF2IP, TERT, familial melanoma, melanoma, spitz melanoma, spitzoid melanoma",

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

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = jun,

doi = "10.1016/j.jdin.2023.01.013",

language = "English (US)",

volume = "11",

pages = "43--51",

journal = "JAAD International",

issn = "2666-3287",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma

T2 - A multi-center case series

AU - Goldstein, Alisa M.

AU - Qin, Richard

AU - Chu, Emily Y.

AU - Elder, David E.

AU - Massi, Daniela

AU - Adams, David J.

AU - Harms, Paul W.

AU - Robles-Espinoza, Carla Daniela

AU - Newton-Bishop, Julia A.

AU - Bishop, D. Timothy

AU - Harland, Mark

AU - Holland, Elizabeth A.

AU - Cust, Anne E.

AU - Schmid, Helen

AU - Mann, Graham J.

AU - Puig, Susana

AU - Potrony, Miriam

AU - Alos, Llucia

AU - Nagore, Eduardo

AU - Millán-Esteban, David

AU - Hayward, Nicholas K.

AU - Broit, Natasa

AU - Palmer, Jane M.

AU - Nathan, Vaishnavi

AU - Berry, Elizabeth G.

AU - Astiazaran-Symonds, Esteban

AU - Yang, Xiaohong R.

AU - Tucker, Margaret A.

AU - Landi, Maria Teresa

AU - Pfeiffer, Ruth M.

AU - Sargen, Michael R.

PY - 2023/6

Y1 - 2023/6

N2 - 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.

AB - 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.

KW - ACD

KW - POT1

KW - TERF2IP

KW - TERT

KW - familial melanoma

KW - melanoma

KW - spitz melanoma

KW - spitzoid melanoma

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UR - http://www.scopus.com/inward/citedby.url?scp=85148652804&partnerID=8YFLogxK

U2 - 10.1016/j.jdin.2023.01.013

DO - 10.1016/j.jdin.2023.01.013

M3 - Article

AN - SCOPUS:85148652804

SN - 2666-3287

VL - 11

SP - 43

EP - 51

JO - JAAD International

JF - JAAD International

ER -

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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