Buller R E, Sood A K, Lallas T, Buekers T, Skilling J S
Department of Pharmacology, The University of Iowa Hospitals and Clinics, Iowa City 52242-1009, USA.
J Natl Cancer Inst. 1999 Feb 17;91(4):339-46. doi: 10.1093/jnci/91.4.339.
Most human female cells contain two X chromosomes, only one of which is active. The process of X-chromosome inactivation, which occurs early in development, is usually random, producing tissues with equal mixtures of cells having active X chromosomes of either maternal or paternal origin. However, nonrandom inactivation may occur in a subset of females. If a tumor suppressor gene were located on the X chromosome and if females with a germline mutation in one copy of that suppressor gene experienced nonrandom X-chromosome inactivation, then some or all of the tissues of such women might lack the wild-type suppressor gene function. This scenario could represent a previously unrecognized mechanism for development of hereditary cancers. We investigated whether such a mechanism might contribute to the development of hereditary ovarian cancers.
Patterns of X-chromosome inactivation were determined by means of polymerase chain reaction amplification of the CAG-nucleotide repeat of the androgen receptor (AR) gene after methylation-sensitive restriction endonuclease digestion of blood mononuclear cell DNA from patients with invasive (n = 213) or borderline (n = 44) ovarian cancer and control subjects without a personal or family history of cancer (n = 50). BRCA1 gene status was determined by means of single-strand conformational polymorphism analysis and DNA sequencing. All statistical tests were two-sided.
Among individuals informative for the AR locus, nonrandom X-chromosome inactivation was found in the DNA of 53% of those with invasive cancer versus 28% of those with borderline cancer (P = .005) and 33% of healthy control subjects (P = .016). Nonrandom X-chromosome inactivation can be a heritable trait. Nine of 11 AR-informative carriers of germline BRCA1 mutations demonstrated nonrandom X-chromosome inactivation (.0002 < P < .008, for simultaneous occurrence of both).
Nonrandom X-chromosome inactivation may be a predisposing factor for the development of invasive, but not borderline, ovarian cancer.
大多数人类女性细胞含有两条X染色体，其中只有一条是活跃的。X染色体失活过程发生在发育早期，通常是随机的，会产生具有母源或父源活跃X染色体的细胞等量混合的组织。然而，非随机失活可能发生在一部分女性中。如果一个肿瘤抑制基因位于X染色体上，并且携带该抑制基因一个拷贝的种系突变的女性经历了非随机X染色体失活，那么这些女性的部分或全部组织可能缺乏野生型抑制基因功能。这种情况可能代表了一种先前未被认识的遗传性癌症发生机制。我们研究了这种机制是否可能导致遗传性卵巢癌的发生。
通过对侵袭性（n = 213）或交界性（n = 44）卵巢癌患者以及无个人或家族癌症病史的对照受试者（n = 50）的血液单核细胞DNA进行甲基化敏感限制性内切酶消化后，利用聚合酶链反应扩增雄激素受体（AR）基因的CAG核苷酸重复序列，来确定X染色体失活模式。通过单链构象多态性分析和DNA测序确定BRCA1基因状态。所有统计检验均为双侧检验。
在对AR基因座有信息价值的个体中，53%的侵袭性癌症患者DNA中发现非随机X染色体失活，而交界性癌症患者为28%（P = .005），健康对照受试者为33%（P = .016）。非随机X染色体失活可能是一种可遗传的性状。11名携带种系BRCA1突变且对AR有信息价值的携带者中有9名表现出非随机X染色体失活（两者同时出现的P值为.0002 < P < .008）。
非随机X染色体失活可能是侵袭性而非交界性卵巢癌发生的一个易感因素。
