FitzGerald M G, Harkin D P, Silva-Arrieta S, MacDonald D J, Lucchina L C, Unsal H, O'Neill E, Koh J, Finkelstein D M, Isselbacher K J, Sober A J, Haber D A
Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8541-5. doi: 10.1073/pnas.93.16.8541.
Five to ten percent of individuals with melanoma have another affected family member, suggesting familial predisposition. Germ-line mutations in the cyclin-dependent kinase (CDK) inhibitor p16 have been reported in a subset of melanoma pedigrees, but their prevalence is unknown in more common cases of familial melanoma that do not involve large families with multiple affected members. We screened for germ-line mutations in p16 and in two other candidate melanoma genes, p19ARF and CDK4, in 33 consecutive patients treated for melanoma; these patients had at least one affected first or second degree relative (28 independent families). Five independent, definitive p16 mutations were detected (18%, 95% confidence interval: 6%, 37%), including one nonsense, one disease-associated missense, and three small deletions. No mutations were detected in CDK4. Disease-associated mutations in p19ARF, whose transcript is derived in part from an alternative codon reading frame of p16, were only detected in patients who also had mutations inactivating p16. We conclude that germ-line p16 mutations are present in a significant fraction of individuals who have melanoma and a positive family history.
5%至10%的黑色素瘤患者有其他受影响的家庭成员，提示存在家族易感性。在一部分黑色素瘤家系中已报道细胞周期蛋白依赖性激酶（CDK）抑制剂p16的种系突变，但在不涉及有多个受影响成员的大家庭的更常见家族性黑色素瘤病例中，其发生率尚不清楚。我们对33例接受黑色素瘤治疗的连续患者筛查了p16以及其他两个候选黑色素瘤基因p19ARF和CDK4的种系突变；这些患者至少有一个受影响的一级或二级亲属（28个独立家庭）。检测到5个独立的、明确的p16突变（18%，95%置信区间：6%，37%），包括1个无义突变、1个与疾病相关的错义突变和3个小缺失。未在CDK4中检测到突变。p19ARF的疾病相关突变，其转录本部分源自p16的一个替代密码子阅读框，仅在同时有使p16失活突变的患者中检测到。我们得出结论，在有黑色素瘤且有阳性家族史的相当一部分个体中存在种系p16突变。
