Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF
Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF
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DOI：
10.1111/bjd.14897
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发表时间：
2016-11-01
影响因子：
10.3
通讯作者：
Puig, S.
中科院分区：
文献类型：
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作者：
Mangas, C.;Potrony, M.;Puig, S.
近10%的皮肤黑色素瘤（CM）病例发生在有个人或家族病史的患者中。目的了解瑞士南部提契诺中高发病率地区CM的遗传易感性。研究人员在多发性原发CMs患者或患有一种或多种CM且有CM或胰腺癌家族史的一或二度亲属中，鉴定了CM高度相关基因（CDKN2A和CDK4）和低/中外显率变异（MC1R和MITF）的种系突变。健康献血者（n = 146）作为对照组。结果2010年7月至2012年7月共纳入患者57例（41个家系）。26例为黑色素瘤易发家族（至少有2例），15例为多发性CMs。在6个家族中发现了胰腺癌。CDKN2A突变p.V126D在7例患者（4个家族）中被鉴定出具有创始人效应，而CDKN2A A148T在7例患者（5个家族）和7例健康供体中被检测到（优势比2.76,95%置信区间0.83-9.20）。在32名患者（78%）和97名健康供者（66%）中检测到至少一种MC1R黑色素瘤相关多态性，在12名患者（29%）和25名健康供者（17%）中检测到超过一种多态性。在另外三个家系的四名患者（7%）和一名健康对照（0.7%）中发现了MITF变体p.E318K。结论：提契诺人群的遗传评估纳入标准应遵循两个规则（一个家庭中的两个受影响个体或患有多种CMs的患者），因为我们在近10%的谱系中（41个中有4个）检测到CDKN2A突变，在7%的谱系中（41个中有3个）检测到MITF p.E318K突变，并且MC1R变异的数量高于对照人群。
Background Nearly 10% of all cases of cutaneous melanoma (CM) occur in patients with a personal or family history of the disease. Objectives To obtain information about genetic predisposition to CM in Ticino, the southern region of Switzerland, a zone with moderate-to-high CM incidence.Methods We identified germline mutations in highly CM-associated genes (CDKN2A and CDK4) and low/medium-penetrance variants (MC1R and MITF) in patients with multiple primary CMs or individuals with one or more CM and a positive family history for CM or pancreatic cancer among first-or second-degree relatives. Healthy blood donors (n = 146) were included as a control group.Results From July 2010 to July 2012, 57 patients (41 pedigrees) were included. Twenty-six were melanoma-prone families (with at least two cases) and 15 had multiple CMs. Pancreatic cancer was found in six families. The CDKN2A mutation p.V126D was identified in seven patients (four families) with a founder effect, whereas CDKN2A A148T was detected in seven cases (five families) and seven healthy donors (odds ratio 2.76, 95% confidence interval 0.83-9.20). At least one MC1R melanoma-associated polymorphism was detected in 32 patients (78%) and 97 healthy donors (66%), with more than one polymorphism in 12 patients (29%) and 25 healthy donors (17%). The MITF variant p.E318K was identified in four patients from three additional pedigrees (7%) and one healthy control (0.7%).Conclusions Inclusion criteria for the Ticino population for genetic assessment should follow the rule of two (two affected individuals in a family or a patient with multiple CMs), as we detected a CDKN2A mutation in almost 10% of our pedigrees (four of 41), MITF p.E318K in 7% (three of 41) and a higher number of MC1R variants than in the control population.