POT1 and multiple primary melanomas: the dermatological phenotype.

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-08-29 DOI:10.1136/jmg-2023-109637
Ellie J Maas, Emily DeBortoli, Vaishnavi Nathan, Ned P Freeman, Adam Mothershaw, Darren J Smit, Brigid Betz-Stablein, Lauren G Aoude, Mitchell S Stark, Richard A Sturm, H Peter Soyer, Aideen M McInerney-Leo
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Abstract

POT1 is the second most frequently reported gene (after CDKN2A) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, POT1 phenotypical reports have been largely restricted to associated malignancies, and description of the dermatological landscape has been limited. We identified 10 variants in n=18 of 384 (4.7%) unrelated individuals (n=13 MPMs; n=5 single primary melanomas) of European ancestry. Five variants were rare (minor allele frequency <0.001) or novel (two loss-of-function (LOF), one splice acceptor and two missense) and were predicted to be functionally significant, in five unrelated probands with MPMs (≥3 melanomas). We performed three-dimensional total body photography on both individuals with confirmed pathogenic LOF variants to characterise the dermatological phenotype. Total body naevus counts (≥2 mm diameter) were significantly higher (p=7.72×10-12) in carriers compared with a control population. Majority of naevi were on the probands' back and lower limb regions, where only mild to moderate ultraviolet (UV) damage was observed. Conversely, the head/neck region, where both probands exhibited severe UV damage, had comparably fewer naevi. We hypothesise that carriage of functionally significant POT1 variants is associated with increased naevus counts generally, and naevi >5 mm in diameter specifically and the location of these are independent of UV damage.

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POT1 和多发性原发性黑色素瘤:皮肤表型。
POT1 是家族性黑色素瘤中第二常见的基因(仅次于 CDKN2A)。致病变体与发病较早和/或多发性原发性黑色素瘤(MPMs)有关。迄今为止,POT1 的表型报告主要局限于相关的恶性肿瘤,对皮肤病的描述也很有限。我们在 384 例(4.7%)无亲属关系的欧洲血统个体(13 例 MPM;5 例单发原发性黑色素瘤)中的 18 例中发现了 10 个变体。与对照人群相比,五个变异在携带者中较为罕见(小等位基因频率×10-12)。大多数黑痣出现在受试者的背部和下肢区域,在这些区域只观察到轻度至中度的紫外线(UV)损伤。相反,头颈部的黑痣数量相对较少,而这两个受试者都有严重的紫外线损伤。我们假设,携带功能显著的 POT1 变体一般与黑痣数量增加有关,特别是与直径大于 5 毫米的黑痣有关,而且这些黑痣的位置与紫外线损伤无关。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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