Exploring the hereditary background of renal cancer in Denmark
Exploring the hereditary background of renal cancer in Denmark
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DOI：
10.1371/journal.pone.0215725
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发表时间：
2019-04-29
期刊：
影响因子：
3.7
通讯作者：
Gerdes, Anne-Marie
中科院分区：
文献类型：
--
作者：
Christensen, Maria Bejerholm;Wadt, Karin;Gerdes, Anne-Marie
背景在丹麦每年有800多名患者被诊断为肾细胞癌（RCC），其中3-5%被认为是遗传性肾癌综合征的一部分。我们进行了遗传筛查的致病性和推定的RCC基因（VHL，FH，FLCN，MET，SDHB，BAP 1，MITF，CDKN 2B）在RCC患者怀疑的遗传predisposition.MethodsThe队列由四十八个丹麦家庭或个人与早发性RCC，RCC家族史，RCC和黑色素瘤或RCC和黑色素瘤诊断在同一个人的家族史。DNA提取从外周血样本或无癌福尔马林固定的石蜡包埋tissue.ResultsOne起始密码子变异的未知临床意义（VUS）（c.3G>A，p.Met1Ile）和一个错义VUS（c.631A>C，p.Met211Leu）被发现在VHL的患者与RCC发病在28岁，但没有其他表现或家族史冯希佩尔林道（VHL）。此外，在三个家族中，我们发现了BAP 1的三种不同变体，其中之一是一个新的非分离错义变体（c.1502G>A，p.Ser501Asn），该家族有两个兄弟患有RCC。最后，我们发现已知的E318 K取代MITF在一个家庭的RCC影响成员与多发性黑色素瘤。结论虽然我们在3个家系中发现了BAP 1的3个VUS，在1个家系中发现了MITF的致病性变异，但BAP 1、MITF或CDKN 2 B的致病性生殖系变异并不是丹麦遗传性肾癌的常见病因。男性、吸烟和肥胖等风险因素的高患病率可能影响了当前研究患者的癌症发展。进一步调查推定的易感基因和危险因素的RCC是必要的，使更好地预测肾癌的风险或症状前检测的亲属在遗传性肾癌家族。
BackgroundEvery year more than 800 patients in Denmark are diagnosed with renal cell carcinoma (RCC) of which 3-5% are expected to be part of a hereditary renal cancer syndrome. We performed genetic screening of causative and putative RCC-genes (VHL, FH, FLCN, MET, SDHB, BAP1, MITF, CDKN2B) in RCC-patients suspected of a genetic predisposition.MethodsThe cohort consisted of forty-eight Danish families or individuals with early onset RCC, a family history of RCC, a family history of RCC and melanoma or both RCC-and melanoma diagnosis in the same individual. DNA was extracted from peripheral blood samples or cancer-free formalin-fixed paraffin-embedded tissue.ResultsOne start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von HippelLindau (VHL). Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC. Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas. No variants were detected in CDKN2B.ConclusionAlthough we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark. It is possible that the high prevalence of risk factors such as male gender, smoking and obesity has influenced the development of cancer in the patients of the current study. Further investigations into putative predisposing genes and risk factors of RCC are necessary to enable better prediction of renal cancer risk or presymptomatic testing of relatives in hereditary renal cancer families.