Begg Colin B, Orlow Irene, Hummer Amanda J, Armstrong Bruce K, Kricker Anne, Marrett Loraine D, Millikan Robert C, Gruber Stephen B, Anton-Culver Hoda, Zanetti Roberto, Gallagher Richard P, Dwyer Terence, Rebbeck Timothy R, Mitra Nandita, Busam Klaus, From Lynn, Berwick Marianne
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Natl Cancer Inst. 2005 Oct 19;97(20):1507-15. doi: 10.1093/jnci/dji312.
Germline mutations in the CDKN2A gene have been linked to melanoma incidence in many families with multiple cases of the disease. Previous studies of multiple-case families have indicated that the lifetime risk (i.e., penetrance) of melanoma in CDKN2A mutation carriers is very high, ranging from 58% in Europe to 91% in Australia by age 80 years. In this study, we examined lifetime melanoma risk among CDKN2A mutation carriers using carriers who were identified in a population-based study of melanoma.
Probands for the study were incident case patients with either first or subsequent melanoma who were identified in nine geographic regions in Australia, Canada, the United States, and Italy. A total of 3626 probands (53% participation rate) with adequate DNA for analysis were recruited and genotyped for CDKN2A mutations. From the 3550 probands whose DNA could be amplified by polymerase chain reaction of CDKN2A exons 1alpha, 2, and 3 and surrounding regions, 65 mutation carriers were identified. Melanoma histories in first-degree relatives of these probands were used to calculate the lifetime risk in CDKN2A mutation carriers using the kin-cohort method.
The risk of melanoma in CDKN2A mutation carriers was approximately 14% (95% CI = 8% to 22%) by age 50 years, 24% (95% CI = 15% to 34%) by age 70 years, and 28% (95% CI = 18% to 40%) by age 80 years. Eighteen probands had three or more first-degree relatives with melanoma, but only one was a carrier of a CDKN2A mutation.
CDKN2A mutation carriers in the general population have a much lower risk of melanoma than that suggested by estimates obtained from multiple-case families. The preponderance of familial clustering of melanoma occurs in families without identifiable mutations in CDKN2A.
在许多有多个黑色素瘤病例的家族中，CDKN2A基因的种系突变与黑色素瘤发病率相关。先前对多病例家族的研究表明，CDKN2A突变携带者患黑色素瘤的终生风险（即外显率）非常高，到80岁时，在欧洲为58%，在澳大利亚为91%。在本研究中，我们使用在一项基于人群的黑色素瘤研究中确定的携带者，来研究CDKN2A突变携带者的终生黑色素瘤风险。
该研究的先证者为在澳大利亚、加拿大、美国和意大利的9个地理区域中确定的初发或继发黑色素瘤病例患者。共招募了3626名有足够DNA用于分析的先证者（参与率为53%），并对其进行CDKN2A突变基因分型。在3550名DNA可通过CDKN2A外显子1α、2和3及周边区域的聚合酶链反应扩增的先证者中，确定了65名突变携带者。这些先证者一级亲属的黑色素瘤病史用于使用亲属队列法计算CDKN2A突变携带者的终生风险。
CDKN2A突变携带者患黑色素瘤的风险在50岁时约为14%（95%可信区间=8%至22%），70岁时为24%（95%可信区间=15%至34%），80岁时为28%（95%可信区间=18%至40%）。18名先证者有三个或更多患黑色素瘤的一级亲属，但只有一名是CDKN2A突变携带者。
一般人群中的CDKN2A突变携带者患黑色素瘤的风险远低于从多病例家族获得的估计值。黑色素瘤家族聚集的主要情况发生在CDKN2A无可识别突变的家族中。
