Monzon J, Liu L, Brill H, Goldstein A M, Tucker M A, From L, McLaughlin J, Hogg D, Lassam N J
Institute of Medical Sciences, University of Toronto, ON, Canada.
N Engl J Med. 1998 Mar 26;338(13):879-87. doi: 10.1056/NEJM199803263381305.
Germ-line mutations in the CDKN2A tumor-suppressor gene (also known as p16, p16INK4a, and MTS1) have been linked to the development of melanoma in some families with inherited melanoma. Whether mutations in CDKN2A confer a predisposition to sporadic (nonfamilial) melanoma is not known. In some patients with sporadic melanoma, one or more additional primary lesions develop, suggesting that some of these patients have an underlying genetic susceptibility to the cancer. We hypothesized that this predisposition might be due to germ-line CDKN2A mutations.
We used the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct DNA sequencing to identify germ-line mutations in the CDKN2A gene in patients with multiple primary melanomas who did not have family histories of the disease. A quantitative yeast two-hybrid assay was used to evaluate the functional importance of the CDKN2A variants.
Of 33 patients with multiple primary melanomas, 5 (15 percent; 95 percent confidence interval, 4 percent to 27 percent) had germ-line CDKN2A mutations. These included a 24-bp insertion at the 5' end of the coding sequence, three missense mutations (Arg24Pro, Met53Ile, and Ser56Ile), and a 2-bp deletion at position 307 to 308 (resulting in a truncated CDKN2A protein). In three families, CDKN2A mutations identical to those in the probands were found in other family members. In two families with mutations, we uncovered previously unknown evidence of family histories of melanoma.
Some patients with multiple primary melanomas but without family histories of the disease have germ-line mutations of the CDKN2A gene. The presence of multiple primary melanomas may signal a genetic susceptibility to melanoma not only in the index patient but also in family members, who may benefit from melanoma-surveillance programs.
在一些遗传性黑色素瘤家族中，细胞周期蛋白依赖性激酶2A（CDKN2A）肿瘤抑制基因（也称为p16、p16INK4a和MTS1）的种系突变与黑色素瘤的发生有关。CDKN2A突变是否会导致散发性（非家族性）黑色素瘤的易感性尚不清楚。在一些散发性黑色素瘤患者中，会出现一个或多个额外的原发性病灶，这表明这些患者中的一些人对该癌症具有潜在的遗传易感性。我们推测这种易感性可能是由于CDKN2A基因的种系突变所致。
我们使用聚合酶链反应、单链构象多态性分析和直接DNA测序来鉴定无黑色素瘤家族病史的多发性原发性黑色素瘤患者CDKN2A基因的种系突变。使用定量酵母双杂交试验评估CDKN2A变体的功能重要性。
在33例多发性原发性黑色素瘤患者中，5例（15%；95%置信区间，4%至27%）存在CDKN2A基因种系突变。这些突变包括编码序列5'端的24bp插入、三个错义突变（Arg24Pro、Met53Ile和Ser56Ile）以及第307至308位的2bp缺失（导致CDKN2A蛋白截短）。在三个家族中，在其他家族成员中发现了与先证者相同的CDKN2A突变。在两个有突变的家族中，我们发现了以前未知的黑色素瘤家族病史证据。
一些无黑色素瘤家族病史的多发性原发性黑色素瘤患者存在CDKN2A基因的种系突变。多发性原发性黑色素瘤的存在可能不仅表明指数患者对黑色素瘤具有遗传易感性，也表明家族成员具有这种易感性，他们可能从黑色素瘤监测计划中受益。
