Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma.
Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma.
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发表时间：
1996-11
期刊：
影响因子：
11.2
通讯作者：
J. Flores;Graeme J. Walker;J. Glendening;F. Haluska;J. Castresana;Rubio Mp;Pastorfide Gc;Boyer La;W. Kao;M. Bulyk;Raymond L. Barnhill;Nicholas K. Hayward;David E. Housman;J. Fountain
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作者：
J. Flores;Graeme J. Walker;J. Glendening;F. Haluska;J. Castresana;Rubio Mp;Pastorfide Gc;Boyer La;W. Kao;M. Bulyk;Raymond L. Barnhill;Nicholas K. Hayward;David E. Housman;J. Fountain
尽管在转移性黑色素瘤细胞系中经常报道 9p21 上的细胞周期蛋白依赖性激酶抑制剂 2 基因 p16INK4a 纯合缺失，并且在家族性黑色素瘤家族中检测到 p16INK4a 基因内的基因内突变，但该基因在体内散发性黑色素瘤发展中的具体靶向仍存在争议。本研究进行了 Southern 分析，初步评估散发性黑色素瘤中 p16INK4a 及其邻近家族成员 p15INK4b 和 9p21 内其他候选区域的半合子或纯合性缺失的频率。总体而言，40 个未培养的散发性黑色素瘤 DNA 中有 22 个 (55%) 被确定含有位于 9p21 上的 1-11 个标记/基因的缺失。这包括 10 个肿瘤（25%；40 个中的 10 个），纯合性缺失仅限于 p16INK4a 基因（20%；10 个中的 2 个）、p16INK4a 和 p15INK4b 基因两者（10%；10 个中的 1 个）、另一个新的 9p21 基因 FB19（10%；10 个中的 1 个）或所有这三个基因加上周围的标记（60%；10 中的 6）。在随后的单链构象多态性和测序分析中，p16INK4a 基因的基因内突变也在两个（10%；21 个）黑色素瘤 DNA 中被发现，保留了该基因座的一个副本。相比之下，黑色素瘤细胞系（平行分析）中p16INK4a和p15INK4b纯合缺失以及p16INK4a突变的频率分别高出2-3倍，分别为61%（38个中的23个）和24%（38个中的9个）。这些发现表明 (a) p16INK4a 在超过四分之一（27.5%；40 例中的 11 例）的散发性黑色素瘤中体内失活； (b) p16INK4a 的突变/缺失可能赋予体外选择性生长优势； (c) 其他 9p21 肿瘤抑制基因可以在黑色素瘤的发展过程中成为靶标。
Although homozygous deletions of the cyclin-dependent kinase inhibitor 2 gene p16INK4a on 9p21 have been reported frequently in metastatic melanoma cell lines, and intragenic mutations within the p16INK4a gene have been detected in familial melanoma kindreds, specific targeting of this gene in the development of sporadic melanoma in vivo remains controversial. Southern analyses were performed in this study to initially assess the frequency of hemi- or homozygous losses of p16INK4a, as well as its neighboring family member, p15INK4b, and other candidate regions within 9p21, in sporadic melanoma. Overall, 22 of 40 (55%) uncultured sporadic melanoma DNAs were determined to harbor deletions of 1-11 markers/genes located on 9p21. This included 10 tumors (25%; 10 of 40) with homozygous deletions limited to either the p16INK4a gene only (20%; 2 of 10), both the p16INK4a and p15INK4b genes (10%; 1 of 10), another novel 9p21 gene, FB19 (10%; 1 of 10), or all three of these genes plus surrounding markers (60%; 6 of 10). In subsequent single-strand conformation polymorphism and sequencing analyses, intragenic mutations in the p16INK4a gene were also revealed in two (10%; 2 of 21) melanoma DNAs that retained one copy of this locus. By comparison, the frequency of pl6INK4a and p15INK4b homozygous deletions, as well as p16INK4a mutations, in melanoma cell lines (analyzed in parallel) was 2-3-fold higher at 61 (23 of 38) and 24% (9 of 38), respectively. These findings indicate that (a) p16INK4a is inactivated in vivo in over one-fourth (27.5%; 11 of 40) of sporadic melanomas; (b) mutation/deletion of p16INK4a may confer a selective growth advantage in vitro; and (c) other 9p21 tumor suppressor genes could be targeted during the development of melanoma.