Figl Adina, Thirumaran Ranjit K, Ugurel Selma, Gast Andreas, Hemminki Kari, Kumar Rajiv, Schadendorf Dirk
Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.
Arch Dermatol. 2007 Apr;143(4):495-9. doi: 10.1001/archderm.143.4.495.
A 19-base pair germline deletion in exon 2 of the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene (Leiden mutation) has been detected in Dutch families with familial melanomas. The penetrance of CDKN2A mutations varies widely and is influenced by environmental and unrelated genetic factors such as variants in the MC1R gene.
We describe a 25-year-old German woman who developed 8 invasive melanomas and 6 in situ melanomas after radiation therapy and polychemotherapy for Hodgkin lymphoma. Genetic testing revealed a constitutional CDKN2A Leiden mutation in the proband and her sister, mother, and mother's sister. The proband also carried high-risk MC1R variant alleles R151C and R160W, which she had inherited from her father and her mother, respectively. The less affected mutation carrier sister did not have high-risk MC1R variant alleles. Analysis of DNA from paraffin-embedded tissues showed loss of heterozygosity at CDKN2A loci in all 3 melanomas studied but not in Hodgkin lymphoma. The pedigree revealed several types of cancers on both sides of the family, but no Dutch ancestors were found. No mutations in the CDK4, B-raf, and N-ras genes were detected either in the germline or in tumors from the patient.
This study shows the variability of the penetrance of the CDKN2A Leiden mutation within the same family, which could be due to genetic or exogenous factors.
在患有家族性黑色素瘤的荷兰家族中，已检测到细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）基因第2外显子中的19个碱基对种系缺失（莱顿突变）。CDKN2A突变的外显率差异很大，并受环境和无关遗传因素（如MC1R基因中的变异）影响。
我们描述了一名25岁的德国女性，她在接受霍奇金淋巴瘤的放疗和多药化疗后，发生了8例浸润性黑色素瘤和6例原位黑色素瘤。基因检测显示，先证者及其姐妹、母亲和母亲的姐妹存在先天性CDKN2A莱顿突变。先证者还携带高风险的MC1R变异等位基因R151C和R160W，分别从父亲和母亲那里遗传而来。受影响较小的突变携带者姐妹没有高风险的MC1R变异等位基因。对石蜡包埋组织的DNA分析显示，在所研究的所有3例黑色素瘤中，CDKN2A基因座存在杂合性缺失，但霍奇金淋巴瘤中未出现。家系显示家族双方有几种类型的癌症，但未发现荷兰祖先。在患者的种系或肿瘤中均未检测到CDK4、B-raf和N-ras基因的突变。
本研究显示了同一家族中CDKN2A莱顿突变外显率的变异性，这可能是由于遗传或外源性因素导致的。
