Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms
Monoallelic silencing and haploinsufficiency in early murine intestinal neoplasms
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DOI：
10.1073/pnas.1120753109
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发表时间：
2012-02-07
影响因子：
11.1
通讯作者：
Dove, William F.
中科院分区：
文献类型：
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作者：
Amos-Landgraf, James M.;Irving, Amy A.;Dove, William F.
对人类家族性腺瘤性息肉病、散发性结肠癌以及小鼠和大鼠肠癌模型的研究表明，大多数早期腺瘤是通过失去腺瘤性息肉病(APC)基因的正常功能而发展起来的。在家族性腺瘤性息肉病小鼠模型中，特别是多发性肠道肿瘤小鼠(Min)和大鼠结肠息肉病(Pirc)大鼠模型中，大多数腺瘤由于同源体细胞重组导致杂合性丢失，导致APC基因的WT拷贝丢失。我们报道在Pirc大鼠的大型结肠腺瘤中，基因组材料中没有可检测到的拷贝数丢失或增加，并且大多数肿瘤仅在18号染色体的短臂上丢失杂合性。对早期小鼠和大鼠肿瘤的检查表明，相当一部分肿瘤显示基因组DNA中APC的杂合性保持不变，显然违反了Knudson的两次命中假说。对大鼠肿瘤样本中的APC基因进行测序，未能在大多数肿瘤中发现维持基因组DNA中APC杂合性的次级突变。利用APC基因的定量等位基因特异性分析，我们发现了两条肿瘤发生的途径。一类肿瘤维持APC(Min/+)或APC(Pirc/+)RNA表达的杂合性，可能与APC功能单倍性不足有关。另一类肿瘤表现出突变的APC等位基因高度偏向的单等位基因表达，为肿瘤抑制基因APC的随机或随机单等位基因沉默过程提供了证据。
Studies of tumors from human familial adenomatous polyposis, sporadic colon cancer, and mouse and rat models of intestinal cancer indicate that the majority of early adenomas develop through loss of normal function of the Adenomatous polyposis coli (APC) gene. In murine models of familial adenomatous polyposis, specifically the multiple intestinal neoplasia mouse (Min) and the polyposis in the rat colon (Pirc) rat, most adenomas have lost their WT copy of the Apc gene through loss of heterozygosity by homologous somatic recombination. We report that large colonic adenomas in the Pirc rat have no detectable copy number losses or gains in genomic material and that most tumors lose heterozygosity only on the short arm of chromosome 18. Examination of early mouse and rat tumors indicates that a substantial subset of tumors shows maintenance of heterozygosity of Apc in genomic DNA, apparently violating Knudson's two-hit hypothesis. Sequencing of the Apc gene in a sampling of rat tumors failed to find secondary mutations in the majority of tumors that maintained heterozygosity of Apc in genomic DNA. Using quantitative allele-specific assays of Apc cDNA, we discovered two neoplastic pathways. One class of tumors maintains heterozygosity of Apc(Min/+) or Apc(Pirc/+) RNA expression and may involve haploinsufficiency for Apc function. Another class of tumors exhibits highly biased monoallelic expression of the mutant Apc allele, providing evidence for a stochastic or random process of monoallelic epigenetic silencing of the tumor suppressor gene Apc.