Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.
Genes Chromosomes Cancer. 2010 May;49(5):425-38. doi: 10.1002/gcc.20753.
We report an investigation of gene dosage at 9p21.3 and mutations in BRAF and NRAS, as predictors of relapse and histological markers of poor melanoma prognosis. Formalin-fixed primary melanomas from 74 relapsed and 42 nonrelapsed patients were sequenced for common BRAF and NRAS mutations (N = 71 results) and gene dosage at 9p21.3 including the genes CDKN2A (which encodes CDKN2A and P14ARF), CDKN2B (CDKN2B), and MTAP was measured using multiplexed ligation-dependant probe amplification (MLPA), (N = 75 results). BRAF/NRAS mutations were detected in 77% of relapsers and 58% of nonrelapsers (Fisher's exact P = 0.17), and did not predict ulceration or mitotic rate. There was no relationship between BRAF/NRAS mutations and gene dosage at 9p21.3. Reduced gene dosage at MTAP showed a borderline association with BRAF mutation (P = 0.04) and reduced gene dosage at the interferon gene cluster was borderline associated with wild type NRAS (P = 0.05). Reduced gene dosage in the CDKN2A regions coding for CDKN2A was associated with an increased risk of relapse (P = 0.03). Reduced gene dosage across 9p21.3 was associated with increased tumor thickness, mitotic rate, and ulceration (P = 0.02, 0.02, and 0.002, respectively), specifically in coding regions impacting on CDKN2B and P14ARF and CDKN2A. Loss at MTAP (P = 0.05) and the interferon gene cluster (P = 0.03) on 9p21 was also associated with tumor ulceration. There was no association between reduced gene dosage at 9p21.3 and subtype or site of tumor. This study presents supportive evidence that CDKN2B, P14ARF, and CDKN2A may all play a tumor suppressor role in melanoma progression.
我们报告了对 9p21.3 基因剂量和 BRAF 和 NRAS 突变的研究，这些是预测黑色素瘤复发和组织学预后不良的标志物。对 74 例复发和 42 例非复发患者的福尔马林固定原发黑色素瘤进行了常见 BRAF 和 NRAS 突变（N = 71 例结果）和 9p21.3 基因剂量（包括编码 CDKN2A 和 P14ARF 的 CDKN2A 基因、CDKN2B 基因和 MTAP 基因）的测序，使用多重连接依赖性探针扩增（MLPA）（N = 75 例结果）。在复发患者中检测到 77%存在 BRAF/NRAS 突变，而非复发患者中则为 58%（Fisher 确切检验 P = 0.17），且这些突变并不能预测溃疡或有丝分裂率。BRAF/NRAS 突变与 9p21.3 基因剂量之间无关联。MTAP 基因剂量降低与 BRAF 突变呈临界关联（P = 0.04），干扰素基因簇基因剂量降低与野生型 NRAS 呈临界关联（P = 0.05）。编码 CDKN2A 的 CDKN2A 区基因剂量降低与复发风险增加相关（P = 0.03）。9p21.3 区域的基因剂量降低与肿瘤厚度增加、有丝分裂率增加和溃疡（P = 0.02、0.02 和 0.002）相关，特别是在影响 CDKN2B 和 P14ARF 和 CDKN2A 的编码区。9p21 上 MTAP（P = 0.05）和干扰素基因簇（P = 0.03）的缺失也与肿瘤溃疡有关。9p21.3 基因剂量降低与肿瘤亚型或部位无关。本研究提供了支持性证据，表明 CDKN2B、P14ARF 和 CDKN2A 可能都在黑色素瘤进展中发挥肿瘤抑制作用。
