Pauliina E Repo, Eveliina Jakkula, Juho Hiltunen, Heidi Putkuri, Aleksandra Staskiewicz-Tuikkanen, Reetta-Stiina Järvinen, Martin Täll, Virpi Raivio, Rana'a T Al-Jamal, Tero T Kivelä, Joni A Turunen
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引用次数: 0
Abstract
Some patients with uveal melanoma (UM) show genetic cancer predisposition: ~2% harbor a pathogenic or likely pathogenic (P/LP) germline variant in BAP1 or, rarely, in 20 other cancer-associated genes. Up to 75% of patients with familial UM (FUM) lack genetic diagnosis, prompting a search beyond BAP1. We studied with exome sequencing blood samples from 106 patients with UM and higher-than-average risk of cancer (UM ≤ 45 years of age, bilateral or familial UM, or personal history of non-ocular cancer) and no P/LP variants in BAP1. Sixteen (15%; 95% confidence interval [CI] 9-23) patients carried at least one P/LP variant in dominant cancer genes (CHEK2, DDX41, FANCM, HOXB13, RAD50, SDHA, SDHB) and fifteen in recessive ones. Only CHEK2 and FANCM have previously been reported in patients with UM. Six patients (6%; 95% CI 2-12) carried multilocus P/LP variants. Their median age at diagnosis of UM was 51 (range, 22-69) years, 9 years less than the cohort median of 60 (range, 13-89). This suggests a role for co-occurring pathogenic variants and potentially multilocus inherited neoplasia allele syndrome (MINAS) in UM predisposition. None with FUM carried P/LP variants, warranting investigation of further genes, lower penetrance variants, and multi-gene heterozygosity in UM predisposition.
一些葡萄膜黑色素瘤(UM)患者表现出遗传性癌症易感性:约2%的患者在BAP1或其他20种癌症相关基因中具有致病性或可能致病性(P/LP)种系变异。高达75%的家族性UM (FUM)患者缺乏基因诊断,这促使人们寻找BAP1以外的基因。我们研究了106例UM患者的外显子组测序血液样本,这些患者的癌症风险高于平均水平(UM≤45岁,双侧或家族性UM,或非眼部癌症的个人病史),并且BAP1中没有P/LP变异。16例(15%;95%可信区间[CI] 9-23)患者携带至少一种显性癌基因(CHEK2、DDX41、FANCM、HOXB13、RAD50、SDHA、SDHB)的P/LP变异,15例患者携带隐性癌基因的P/LP变异。此前只有CHEK2和FANCM在UM患者中被报道过。6例患者(6%;95% CI 2-12)携带多位点P/LP变异。他们诊断为UM时的中位年龄为51岁(范围22-69岁),比队列中位年龄60岁(范围13-89岁)小9岁。这表明共同发生的致病变异和潜在的多位点遗传性肿瘤等位基因综合征(MINAS)在UM易感性中的作用。FUM患者均未携带P/LP变异,因此需要进一步研究UM易感性的基因、低外显率变异和多基因杂合性。
期刊介绍:
Pigment Cell & Melanoma Researchpublishes manuscripts on all aspects of pigment cells including development, cell and molecular biology, genetics, diseases of pigment cells including melanoma. Papers that provide insights into the causes and progression of melanoma including the process of metastasis and invasion, proliferation, senescence, apoptosis or gene regulation are especially welcome, as are papers that use the melanocyte system to answer questions of general biological relevance. Papers that are purely descriptive or make only minor advances to our knowledge of pigment cells or melanoma in particular are not suitable for this journal. Keywords
Pigment Cell & Melanoma Research, cell biology, melatonin, biochemistry, chemistry, comparative biology, dermatology, developmental biology, genetics, hormones, intracellular signalling, melanoma, molecular biology, ocular and extracutaneous melanin, pharmacology, photobiology, physics, pigmentary disorders