Unit of Cancer Genetics, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Traversa La Crucca 3, Baldinca Li Punti 07100, Sassari, Italy.
J Transl Med. 2013 Aug 29;11:202. doi: 10.1186/1479-5876-11-202.
Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population.
Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening.
Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients' geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases.
Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease.
在意大利同一人群中，对来自不同地域的晚期黑色素瘤患者的多个黑色素瘤病变中 BRAF 和 NRAS 基因的致病突变的流行率和分布进行了评估。
通过自动直接测序，对 513 例连续收集的晚期黑色素瘤（AJCC 分期 III 和 IV 期）患者的总共 749 个肿瘤样本（451 个原发性肿瘤和 298 个转移灶）的基因组 DNA 进行了 BRAF 基因外显子 15 和 NRAS 基因整个编码 DNA 的突变筛查。在组织中，包括 236 对原发性黑色素瘤和同步或异步转移灶的样本。
总体而言，BRAF 基因在 49%的原发性黑色素瘤和 51%的转移灶中，NRAS 基因在 15%的原发性肿瘤和 16%的继发性肿瘤中检测到突变。根据患者的地域来源，在 451 例原发性黑色素瘤中观察到这两种基因的突变分布不均：BRAF 突变患者分别为 61%和 42%（p = 0.0372），NRAS 突变患者分别为 2%和 21%（p < 0.0001）。在撒丁岛和非撒丁岛人群中分别观察到淋巴结（91%）和内脏转移灶（92.5%）中配对样本的 BRAF/NRAS 突变一致性较高，但脑转移灶（79%；p = 0.0227）和皮肤转移灶（71%；p = 0.0009）的突变一致性明显较低。
我们关于晚期黑色素瘤患者不同肿瘤组织中发生的两种主要改变的发现，可能有助于改善对这种疾病的治疗管理。
