Goldstein A M, Stacey S N, Olafsson J H, Jonsson G F, Helgason A, Sulem P, Sigurgeirsson B, Benediktsdottir K R, Thorisdottir K, Ragnarsson R, Kjartansson J, Kostic J, Masson G, Kristjansson K, Gulcher J R, Kong A, Thorsteinsdottir U, Rafnar T, Tucker M A, Stefansson K
Genetic Epidemiology Branch, Division of Cancer Epidemiologyand Genetics/NCI/NIH/DHHS, Executive Plaza South, Room 7004, 6120 Executive Blvd MSC 7236, Bethesda, MD 20892-7236, USA.
J Med Genet. 2008 May;45(5):284-9. doi: 10.1136/jmg.2007.055376. Epub 2008 Jan 4.
Germline CDKN2A mutations have been observed in 20-40% of high risk, melanoma prone families; however, little is known about their prevalence in population based series of melanoma cases and controls.
We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry ascertained melanoma cases and 691 population based controls from Iceland, a country in which the incidence of melanoma has increased rapidly.
We identified a novel germline variant, G89D, that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head and neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma.
This population based study of Icelandic melanoma cases and controls showed a frequency of disease related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consist of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population based estimates of CDKN2A mutation frequencies are available.
在20% - 40%的高危、易患黑色素瘤的家族中观察到种系CDKN2A突变；然而，对于其在基于人群的黑色素瘤病例系列和对照中的患病率知之甚少。
我们对约703例登记确诊的黑色素瘤病例和691例来自冰岛的基于人群的对照进行了CDKN2A基因重测序，包括p14ARF变体和启动子区域，冰岛是一个黑色素瘤发病率迅速上升的国家。
我们鉴定出一种新的种系变体G89D，它与黑色素瘤风险增加密切相关，似乎是冰岛的一个始祖突变。G89D变体存在于约2%的冰岛侵袭性皮肤恶性黑色素瘤病例中。与其他黑色素瘤患者的亲属相比，受影响的G89D携带者的亲属患黑色素瘤、头颈癌和胰腺癌的风险显著增加。还鉴定出了其他19种种系变体，但没有一种明确增加黑色素瘤风险。
这项基于冰岛黑色素瘤病例和对照的人群研究显示，与疾病相关的CDKN2A突变等位基因频率在0.7%至1.0%之间，从而扩展了我们对不同人群中CDKN2A突变频率的认识。与在北美和澳大利亚观察到的广泛突变谱且频率相似不同，在冰岛，功能性CDKN2A突变仅由一两种不同变体组成。其他遗传和/或环境因素可能对解释冰岛黑色素瘤的高发病率至关重要。这项研究增加了有基于人群的CDKN2A突变频率估计的地理区域。
