Chromosomal instability in MYH- and APC-mutant adenomatous polyps
Chromosomal instability in MYH- and APC-mutant adenomatous polyps
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DOI：
10.1158/0008-5472.can-05-2407
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Fodde, R
中科院分区：
文献类型：
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作者：
Cardoso, J;Molenaar, L;Fodde, R
绝大多数结直肠癌显示遗传不稳定性，无论是在染色体不稳定性（CIN）或微卫星不稳定性（MIN）的形式。尽管CIN肿瘤是非整倍体，但由错配修复功能丧失引起的MIN结直肠癌通常接近二倍体。最近，MYH基因的双等位基因生殖系突变被发现与AIM相关息肉病（MAP）有关，这是一种常染色体隐性遗传的多发性结直肠息肉病，通常与遗传性APC突变引起的显性家族性腺瘤性息肉病（FAP）综合征难以区分。在这里，我们分析MYH和APC突变息肉相结合的激光捕获显微切割，等温基因组DNA扩增，和阵列比较基因组杂交。将平滑分位数回归方法应用于MAP和FAP基因组谱，以区分主要受增益和损失影响的染色体。高达80%和60%的MAP和FAP息肉分别显示异倍体改变。MAP和FAP腺瘤的特征都是染色体1p、17、19和22的频繁丢失和影响染色体7和13的增益。在AIM驱动的肿瘤发生的早期阶段检测到的非整倍体变化可能是MAP中肿瘤进展加速、癌症风险增加和预后不良的基础。
The vast majority of colorectal cancers display genetic instability, either in the chromosomal instability (CIN) or microsatellite instability (MIN) forms. Although CIN tumors are per definition aneuploid, MIN colorectal cancers, caused by loss of mismatch repair function, are usually near diploid. Recently, biallelic germ line mutations in the MYH gene were found to be responsible for AIM-associated polyposis (MAP), an autosomal recessive predisposition to multiple colorectal polyps, often indistinguishable from the dominant familial adenomatous polyposis (FAP) syndrome caused by inherited APC mutations. Here, we analyzed MYH- and APC-mutant polyps by combining laser capture microdissection, isothermal genomic DNA amplification, and array comparative genomic hybridization. Smoothed quantile regression methods were applied to the MAP and FAP genomic profiles to discriminate chromosomes predominantly affected by gains and losses. Up to 80% and 60% of the MAP and FAP polyps showed aneuploid changes, respectively. Both MAP and FAP adenomas were characterized by frequent losses at chromosome 1p, 17, 19, and 22 and gains affecting chromosomes 7 and 13. The aneuploid changes detected at early stages of AIM-driven tumorigenesis may underlie accelerated tumor progression, increased cancer risk, and poor prognosis in MAP.