Seemanová Eva, Jarolim Petr, Seeman Pavel, Varon Raymonda, Digweed Martin, Swift Michael, Sperling Karl
DrSc, Department of Clinical Genetics, Charles University Hospital, 2nd Medical School of Charles University, V úvalu 84, 150 06 Praha 5 Motol, Czech Republic.
J Natl Cancer Inst. 2007 Dec 19;99(24):1875-80. doi: 10.1093/jnci/djm251. Epub 2007 Dec 11.
The autosomal recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) is associated with increased risk of lymphoid malignancies and other cancers. Cells from NBS patients contain many double-stranded DNA breaks. More than 90% of NBS patients are homozygous for a founder mutation, 657del5, in the NBN gene. We investigated the 657del5 carrier status of cancer patients among blood relatives (i.e., first-, through fourth-degree relatives) of NBS patients in the Czech Republic and Slovakia to test the hypothesis that NBN heterozygotes have an increased cancer risk.
Medical information was compiled from 344 blood relatives of NBS patients in 24 different NBS families from January 1, 1998, through December 31, 2003. The 657del5 carrier status of subjects was unknown at the time of their recruitment but was later determined from blood samples collected at the time of the interview. Medical records and death certificates were used to confirm a diagnosis of cancer. For the relatives with cancer who are not obligate heterozygotes (such as parents and two grandparents in consanguineous families), the observed and expected number of mutation carriers were compared by use of the index-test method, which estimated the risk of cancer associated with carrying the mutation. All P values were two-sided.
Thirteen of the 344 blood relatives had confirmed cases of any type of cancer; 11 of these 13 cancer patients carried the NBN 657del5 mutation, compared with 6.0 expected (P = .005). Among the 56 grandparents with complete data from 14 NBS families, 10 of the 28 carriers of 657del5, but only one of the 28 noncarriers, developed cancer (odds ratio = 10.7, 95% CI = 1.4 to 81.5; P<.004).
The NBN 657del5 mutation appears to be associated with an elevated risk of cancer in heterozygotes.
常染色体隐性染色体不稳定疾病尼杰梅亨断裂综合征（NBS）与淋巴系统恶性肿瘤及其他癌症的风险增加相关。NBS患者的细胞含有许多双链DNA断裂。超过90%的NBS患者在NBN基因中存在一个奠基者突变657del5的纯合子。我们调查了捷克共和国和斯洛伐克NBS患者的血亲（即一级至四级亲属）中癌症患者的657del5携带状态，以检验NBN杂合子患癌风险增加这一假设。
收集了1998年1月1日至2003年12月31日期间来自24个不同NBS家庭的344名NBS患者血亲的医疗信息。受试者的657del5携带状态在招募时未知，但后来通过访谈时采集的血样确定。医疗记录和死亡证明用于确诊癌症。对于非必然杂合子的癌症亲属（如近亲家庭中的父母和两位祖父母），使用指数检验法比较观察到的和预期的突变携带者数量，该方法估计了携带突变与患癌风险的相关性。所有P值均为双侧。
344名血亲中有13人确诊患有任何类型的癌症；这13名癌症患者中有11人携带NBN 657del5突变，而预期为6.0人（P = .005）。在来自14个NBS家庭且有完整数据的56名祖父母中，28名657del5携带者中有10人患癌，但28名非携带者中只有1人患癌（优势比 = 10.7，95%可信区间 = 1.4至81.5；P<.004）。
NBN 657del5突变似乎与杂合子患癌风险升高相关。
