Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps
Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps
复制标题
APC 等位基因调节导致结肠息肉的突变频率和类别
作者：
L. Spirio;W. Samowitz;J. Robertson;M. Robertson;R. Burt;M. Leppert;Raymond White
大肠腺瘤病息肉病基因（APC）的大多数遗传突变等位基因导致大量结肠息肉的出现，即家族性息肉病综合征。（这些突变等位基因被命名为APC P等位基因。）APC突变的一个子集，即衰减型或APC AP等位基因，仅易患少数结肠息肉。这就产生了一种假设，即如果遗传正常等位基因的突变在息肉发育中是限速的，那么与APCP等位基因相关的息肉数量的增加表明，APCP携带者中导致息肉形成的突变频率高于APCAP携带者。我们之前已经提出APC蛋白可能调节突变的频率，如杂合性（LOH）的丧失，这是结肠息肉形成所必需的。因此，我们推断，与携带APCP等位基因的患者相比，携带APCAP等位基因的患者的肿瘤可能显示出更低的LOH频率。AAPC突变等位基因的丢失被指定为LOH AP。与未选择的息肉病患者组相比，筛选APCAP携带者的肿瘤显示LOH降低。事实上，虽然测序显示遗传APCN等位基因在肿瘤中经常发生点突变和小缺失，但没有观察到遗传APCN等位基因的丢失。遗传的APCAP等位基因出现低频丢失。这些发现支持了APCAP等位基因具有残留基因活性的观点，这种活性调节了导致腺瘤形成的突变的频谱和频率。
Most inherited mutant alleles of the adenomatosis polyposis coli gene (APC) cause the appearance of large numbers of colon polyps, the familial polyposis syndrome. (These mutant alleles are designated APC P alleles.) A subset of APC mutations, the attenuated or APC AP alleles, predispose to only a few colon polyps. This leads to the hypothesis that if mutation of the inherited normal allele is rate limiting in polyp development, the increased number of polyps associated with the APCP allele indicates that the frequency of mutations that can lead to polyp formation is higher among APCP carriers than among APCAP carriers. We have previously suggested that the APC protein might modulate the frequency of mutations, such as loss of heterozygosity (LOH), necessary for colon polyp formation. We thus reasoned that tumours from patients who carry an APCAP allele might show a reduced frequency of LOH compared with tumours from patients who carry an APCP allele. Loss of AAPC mutant alleles is designated as LOH AP. Screening of tumours from APCAP carriers revealed a reduction of LOH compared with that of an unselected group of polyposis patients. In fact, no loss of the inherited APCN allele was observed, although sequencing showed that the inherited APCN allele had frequently undergone point mutations and small deletions in the tumours. A low frequency loss of the inherited APCAP allele was seen. These findings support the suggestion that the APCAP allele has residual gene activity and that this activity modulates the spectrum and frequency of mutations that lead to adenoma formation.
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影响因子：
56.9
作者：
NISHISHO, I;NAKAMURA, Y;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
映射到人类染色体 1P35-36 的三个分泌性磷脂酶 A(2) 基因在患有减毒腺瘤性结肠息肉病的个体中没有突变。
影响因子：
11.2
作者：
Spirio,LN;Kutchera,W;Winstead,MV;Pearson,B;Kaplan,C;Robertson,M;Lawrence,E;Burt,RW;Tischfield,JA;Leppert,MF;Prescott,SM;White,R
通讯作者：
White,R
影响因子：
29.4
作者：
SAMOWITZ, WS;SLATTERY, ML;KERBER, RA
通讯作者：
KERBER, RA
影响因子：
158.5
作者：
POWELL, SM;PETERSEN, GM;KINZLER, KW
通讯作者：
KINZLER, KW
影响因子：
56.9
作者：
KINZLER, KW;NILBERT, MC;NAKAMURA, Y
通讯作者：
NAKAMURA, Y