Evolution of intratumoral genetic heterogeneity during colorectal cancer progression
Evolution of intratumoral genetic heterogeneity during colorectal cancer progression
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DOI：
10.1093/carcin/bgi044
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发表时间：
2005-05-01
期刊：
影响因子：
4.7
通讯作者：
Benhattar, J
中科院分区：
文献类型：
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作者：
Losi, L;Baisse, B;Benhattar, J
到目前为止，结直肠癌进展过程中肿瘤内遗传异质性的演变还没有得到研究。对早期、晚期和转移结直肠腺癌的多个样本区域进行了众所周知的遗传改变的研究：K-ras和P53点突变以及染色体5q和18q上的杂合性丢失(LOH)。在原发结直肠癌(CRC)中，肿瘤内遗传异质性在早期比晚期更常见，分别为90%和67%。除一例外，所有晚期癌均由一个优势克隆和其他次要克隆组成，而在半数早期癌中未发现优势克隆。在早期阶段，最后产生的事件，即P53突变和18q的LOH，也是最具异质性的。在晚期，5q和18q的杂合性缺失是最常见的异质性事件(分别为67%和58%)。从早期到晚期，肿瘤内突变的异质性显著降低(K-ras从60%到20%，p53从70%到20%)。另一方面，在远处转移中观察到K-ras和P53的肿瘤内遗传异质性几乎不存在。总而言之，结直肠腺癌具有显著的肿瘤内遗传异质性。点突变的瘤内遗传异质性的降低和等位基因丢失的异质性的相对稳定表明，在结直肠癌的进展过程中，克隆选择和染色体不稳定性仍在继续，但尚不能证明增加。
Evolution of intratumoral genetic heterogeneity during colorectal tumor progression has not been investigated so far. Multiple sample areas in colorectal adenocarcinoma at early and advanced stages and in metastases were studied for the well-known genetic alterations: K-ras and p53 point mutations and loss of heterozygosity (LOH) on chromosomes 5q and 18q. In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. At the early stage, the last events that were produced, the p53 mutation and LOH of 18q, were also the most heterogeneous. At the advanced stage, the LOH of 5q and 18q were the most frequent heterogeneous events (67 and 58%, respectively). The intratumoral heterogeneity for mutations was significantly reduced, from the early to the advanced stages (from 60 to 20% for K-ras and from 70 to 20% for p53). On the other hand, a quasi absence of intratumoral genetic heterogeneity was observed for K-ras and p53 in distant metastasis. In conclusion, colorectal adenocarcinomas are characterized by marked intratumoral genetic heterogeneity. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.