Instability of X chromosome methylation in aberrant crypt foci of the human colon.
Instability of X chromosome methylation in aberrant crypt foci of the human colon.
复制标题
人类结肠异常隐窝灶中 X 染色体甲基化的不稳定性。
作者：
Nobuyuki Sakurazawa;N. Tanaka;M. Onda;Hiroyasu Esumi
长期以来，结肠中的异常隐窝病灶(ACF)一直被认为是癌前病变，因此是单克隆性的，但这一问题尚未解决。从5例女性患者中分离出11株ACF。从这些ACF中，获得了178个个体异常隐窝(ACS)，并使用一种基于X染色体上多态X-连锁人雄激素受体(HUMARA)基因失活的方法来评估其克隆性。10株ACF为单克隆型和多克隆型的混合型。Humara分析表明，几乎所有ACF都是多克隆病变。同时，我们研究了每个AC中的K-ras突变。我们发现7个ACF含有K-ras突变；令人惊讶的是，这与来自单个ACF的所有ACS一致。这些结果与Humara分析结果相反，表明ACF病变是单克隆性的。这一差异表明ACF明显是多克隆的，因为活性X染色体上的从头甲基化。为了证实这一可能性，我们使用竞争性PCR方法研究了男性ACF中X染色体的甲基化状态。从4名男性患者的8个ACF中分离出119个个体的ACS。在119例男性急性冠脉综合征患者中，共有47例(39%)HUMARA基因发生从头甲基化。我们发现8例男性ACF中有6例含有K-ras突变，这与同一ACF的所有ACS都是一致的。我们得出结论，X染色体甲基化在ACF中是不稳定的，这可能是结肠癌发生的早期事件。
Aberrant crypt foci (ACF) in the colon have long been thought to be precancerous lesions and therefore monoclonal, but this is unresolved. Eleven ACF were isolated from five female patients. From these ACF, 178 individual aberrant crypts (ACs) were obtained and assessed for clonality using a method based on X chromosome inactivation of the polymorphic X-linked human androgen receptor (HUMARA) gene. Ten ACF were found to be mixtures of monoclonal and polyclonal types. The HUMARA analysis indicated that almost all ACF were polyclonal lesions. Simultaneously, we investigated K-ras mutations in each AC. We found that seven of the ACF harbored the K-ras mutation; strikingly, this was concordant for all of the ACs from a single ACF. These results, by contrast to the results of HUMARA analysis indicate that ACF lesions are monoclonal. This discrepancy suggests that ACF are apparently polyclonal because of de novo methylation on the active X chromosome. To confirm this possibility, we investigated the methylation status of the X chromosome in male ACF using a competitive PCR assay. One hundred nineteen individual ACs were isolated from eight ACF derived from four male patients. A total of 47 of 119 (39%) of male ACs showed de novo methylation of the HUMARA gene. We found that six of the eight male ACF harbored the K-ras mutation, and this was concordant for all of the ACs from a single ACF. We conclude that X chromosome methylation is unstable in ACF and that this might be an early event in colon carcinogenesis.
影响因子：
56.9
作者：
FEARON, ER;HAMILTON, SR;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
11.2
作者：
T. P. Pretlow;B. J. Barrow;VV. Scott Ashton;M. O'riordan;T. Pretlow;J. Jurcisek;T. Stellato
通讯作者：
T. P. Pretlow;B. J. Barrow;VV. Scott Ashton;M. O'riordan;T. Pretlow;J. Jurcisek;T. Stellato
影响因子：
56.9
作者：
VOGELSTEIN, B;FEARON, ER;FEINBERG, AP
通讯作者：
FEINBERG, AP