Germline cancer susceptibility in individuals with melanoma - 04/05/24

Doi : 10.1016/j.jaad.2023.11.070

Pauline Funchain, MD ^a,^⁎ , Ying Ni, PhD ^b, Brandie Heald, MS, CGC ^c,^d, Brandon Bungo, MD ^e, Michelle Arbesman, BS ^a, Tapas R. Behera, MD ^a,^b, Shelley McCormick, MS, LCGC ^f, Jung Min Song, APRN, CNS ^a,^g, Lucy Boyce Kennedy, MD ^a, Sarah M. Nielsen, MS, CGC ^d, Edward D. Esplin, MD, PhD ^d, Emily Nizialek, MD, PhD ^h, Jennifer Ko, MD, PhD ^i,^j, Claudia M. Diaz-Montero, PhD ^b, Brian Gastman, MD ^k, Alexander J. Stratigos, MD ^l, Mykyta Artomov, PhD ^m, Hensin Tsao, MD PhD ⁿ, Joshua Arbesman, MD ^k
^a Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio
^b Center for Immunotherapy & Precision Immuno-Oncology, Cleveland Clinic Foundation, Cleveland, Ohio
^c Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio
^d Invitae Corporation, South San Francisco, California
^e Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio
^f Center Cancer Risk Assessment, Massachusetts General Hospital, Cambridge, Massachusetts
^g Department of Hematology/Oncology, MetroHealth, Cleveland, Ohio
^h Department of Medical Oncology, Johns Hopkins University, Baltimore, Maryland
ⁱ The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio
^j Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio
^k Dermatology and Plastic Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
^l Department of Dermatology-Venereology, A. Sygros Hospital Medical School, University of Athens, Athens, Greece
^m Broad Institute, Cambridge, Massachusetts
ⁿ Department of Dermatology, Massachusetts General Hospital, Cambridge, Massachusetts

^∗Correspondence to: Pauline Funchain, MD, Stanford University School of Medicine, 269 Campus Dr, Rm 1115 (MC:5151), Stanford, CA 94305.Stanford University School of Medicine269 Campus DrRm 1115 (MC:5151)StanfordCA94305

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 04 May 2024

Abstract

Background

Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers.

Objective

To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma.

Methods

Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets.

Results

Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study.

Limitations

Cohorts with varying degrees of selection, some retrospective.

Conclusion

Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

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Key words : cancer predisposition, DNA repair, familial melanoma, family history, genetic testing, germline, homologous repair deficiency, inherited cancer syndromes, melanoma

Abbreviations used : AJ, BA, GMFR, HRD, INV, P/LP, TGCA

Plan

Introduction

Methods

Prospective registry cohort

Comparison cohorts from publicly available databases

Germline variant analysis

Statistical analysis

Results

Germline variants in a selected multidisciplinary melanoma population

Comparison to existing melanoma and nonmelanoma data sets

Discussion

	Funding sources: Supported by Gross Family Melanoma Registry.
	This work was previously presented in part at the ASCO Annual Meeting in the Poster Discussion of the Prevention, Risk Reduction and Hereditary Cancer Session on June 6, 2022, Chicago, IL.
	Patient consent: No identifiable photographic material has been included as part of the publication. Consent for overall participation in the study and its published results was obtained from all participants by the authors as per IRB requirements.
	IRB approval status: This study was granted approval from both the Cleveland Clinic IRB (#17-887) and the Protocol Review and Monitoring Committee of the Case Comprehensive Cancer Center (CASE 1617).