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Brief Report
December 26, 2018

Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma

Author Affiliations
  • 1Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, England
  • 2Laboratorio Internacional de Investigación sobre el Genoma Humano, Universidad Nacional Autónoma de México, Campus Juriquilla, Santiago de Querétaro, Qro, Mexico
  • 3Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain
  • 4Centro de Investigación en Red de Cáncer (CIBERONC), Madrid, Spain
  • 5Melanoma Unit, Department of Dermatology, Hospital Clínic de Barcelona, IDIBAPS, Barcelona University, Barcelona, Spain
  • 6Centre of Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
  • 7Biochemistry and Molecular Genetics Department, Melanoma Unit, Hospital Clínic de Barcelona, IDIBAPS, Barcelona University, Barcelona, Spain
  • 8Gustave Roussy, Université Paris-Saclay, Département de Biologie et Pathologie Médicales, Villejuif, France
  • 9INSERM U1186, Université Paris-Saclay, Villejuif, France
  • 10Département de Génétique, APHM, CHU Timone-Enfants, Marseille, France
  • 11Department of Pathology Brigham & Women’s Hospital, Boston Massachusetts
  • 12Pathology Department, Western General Hospital, Edinburgh, Scotland
  • 13Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, England
  • 14Department of Pathology, University of Michigan, Ann Arbor
  • 15Department of Dermatology, University of Michigan, Ann Arbor
JAMA Dermatol. 2019;155(5):604-609. doi:10.1001/jamadermatol.2018.3662
Key Points

Question  What is the association of the p.I78T variant in the Protection of Telomeres 1 gene (POT1) with familial melanoma?

Findings  We identified the POT1 p.I78T variant in 3 families of Jewish heritage with melanoma in the family and provide evidence that p.I78T interferes with POT1-telomere binding, a critical disruption associated with tumor predisposition. These findings suggest that the POT1 p.I78T variant may represent a founder allele.

Meaning  The identification of high-penetrance germline variants, such as POT1 p.I78T, facilitates screening and counseling of at-risk patients.


Importance  The protection of telomeres 1 protein (POT1) is a critical component of the shelterin complex, a multiple-protein machine that regulates telomere length and protects telomere ends. Germline variants in POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of cancers including cutaneous T-cell lymphoma (CTCL).

Objective  To characterize pathogenic variation in POT1 in families with melanoma to inform clinical management.

Design, Setting, and Participants  In this case study and pedigree evaluation, analysis of the pedigree of 1 patient with melanoma revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) that was subsequently found in 2 other pedigrees obtained from the GenoMEL Consortium.

Main Outcomes and Measures  (1) Identification of the POT1 p.I78T variant; (2) evaluation of the clinical features and characteristics of patients with this variant; (3) analysis of 3 pedigrees; (4) genomewide single-nucleotide polymorphism genotyping of germline DNA; and (5) a somatic genetic analysis of available nevi and 1 melanoma lesion.

Results  The POT1 p.I78T variant was found in 3 melanoma pedigrees, all of persons who self-reported as being of Jewish descent, and was shown to disrupt POT1-telomere binding. A UV mutation signature was associated with nevus and melanoma formation in POT1 variant carriers, and somatic mutations in driver genes such as BRAF, NRAS, and KIT were associated with lesion development in these patients.

Conclusions and Relevance  POT1 p.I78T is a newly identified, likely pathogenic, variant meriting screening for in families with melanoma after more common predisposition genes such as CDKN2A have been excluded. It could also be included as part of gene panel testing.