Gillanders Elizabeth, Juo Suh-Hang Hank, Holland Elizabeth A, Jones MaryPat, Nancarrow Derek, Freas-Lutz Diana, Sood Raman, Park Naeun, Faruque Mezbah, Markey Carol, Kefford Richard F, Palmer Jane, Bergman Wilma, Bishop D Timothy, Tucker Margaret A, Bressac-de Paillerets Brigitte, Hansson Johan, Stark Mitchell, Gruis Nelleke, Bishop Julia Newton, Goldstein Alisa M, Bailey-Wilson Joan E, Mann Graham J, Hayward Nicholas, Trent Jeffrey
Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD.
Am J Hum Genet. 2003 Aug;73(2):301-13. doi: 10.1086/377140. Epub 2003 Jul 3.
Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.
在过去20年里，皮肤恶性黑色素瘤（CMM）的发病率在全球范围内急剧上升。该病的阳性家族史是CMM最确定的危险因素之一；据估计，10%的CMM病例是由遗传易感性导致的。尽管已证明两个基因CDKN2A和CDK4的突变会增加患CMM的风险，但它们仅占有多例CMM病例的家族的20%-25%。因此，为了定位其他与黑色素瘤易感性相关的基因座，我们对49个澳大利亚家系进行了全基因组连锁扫描，这些家系至少有3例CMM病例，且已排除CDKN2A和CDK4的参与。在D1S2726处获得了最高的两点参数LOD分数（1.82；重组分数[θ]0.2），该基因座位于1号染色体短臂（1p22）上。在9个发病年龄较早的家系中，D1S2779处的参数LOD分数为4.
