What is the association of the p.I78T variant in the Protection of Telomeres 1 gene (POT1) with familial melanoma?
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.
The identification of high-penetrance germline variants, such as POT1 p.I78T, facilitates screening and counseling of at-risk patients.
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).
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.
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.
Wong K, Robles-Espinoza CD, Rodriguez D, et al. Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma. JAMA Dermatol. 2019;155(5):604–609. doi:10.1001/jamadermatol.2018.3662
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