Nagel S, Borisch B, Thein S L, Oestreicher M, Nöthiger F, Birrer S, Tobler A, Fey M F
Division for Clinical and Experimental Research, Inselspital, Berne, Switzerland.
Cancer Res. 1995 Jul 1;55(13):2866-70.
We investigated clonal intratumor heterogeneity by comparing different areas of each tumor in 20 gastrointestinal cancers from female patients (1 esophageal cancer, 5 stomach cancers, and 14 colorectal cancers). In all 19 cases informative for X-inactivation analysis with the M27 beta and/or the phosphoglycerate kinase probes, the tumors were clonal. Separate areas from a given tumor showed identical X-inactivation patterns, providing evidence for its single-cell origin. Of 20 cancers, 11 showed p53 gene mutations (base pair insertions, point mutations, and one case of a base pair deletion) in exons 5-8. A particular p53 gene mutation was identical in all tumor areas investigated per case. The minisatellite probes detected loss of heterozygosity or new mutant alleles at 1p33, 1q21, 5q35, 17p13, or 18q21. In seven cases mutations at particular loci were restricted to one or two areas per tumor, while in another seven cases they were common to all tumor areas. Loss of heterozygosity or new alleles detected at the microsatellite loci D2S123, D3S1611, D5S107, D17S261, or D18S34 [(CA)n repeats] were common to all tumor areas in 7 of 19 cases. In another seven cases, however, microsatellite mutations at these loci were restricted to one to three areas per tumor. Tracing clonal intratumor heterogeneity would permit one to study the hierarchy of mutational events in cancers where no premalignant lesions can be harvested. Most important, our study indicates that clonal intratumor heterogeneity might lead to sampling errors in the molecular diagnosis of cancer biopsy specimens when using mini- or microsatellite markers.
我们通过比较20例女性胃肠道癌（1例食管癌、5例胃癌和14例结直肠癌）每个肿瘤的不同区域，研究了肿瘤内克隆异质性。在所有19例可用M27β和/或磷酸甘油酸激酶探针进行X染色体失活分析的病例中，肿瘤均为克隆性。来自给定肿瘤的不同区域显示出相同的X染色体失活模式，为其单细胞起源提供了证据。在20例癌症中，11例在第5至8外显子中出现p53基因突变（碱基对插入、点突变以及1例碱基对缺失）。每个病例中，所有研究的肿瘤区域的特定p53基因突变均相同。微卫星探针检测到在1p33、1q21、5q35、17p13或18q21处杂合性缺失或新的突变等位基因。在7例病例中，特定位点的突变局限于每个肿瘤的一两个区域，而在另外7例病例中，这些突变在所有肿瘤区域均有出现。在19例病例中的7例中，在微卫星位点D2S123、D3S1611、D5S107、D17S261或D18S34[（CA）n重复序列]检测到的杂合性缺失或新等位基因在所有肿瘤区域均有出现。然而，在另外7例病例中，这些位点的微卫星突变局限于每个肿瘤的一至三个区域。追踪肿瘤内克隆异质性将使人们能够研究无法获取癌前病变的癌症中突变事件的层级关系。最重要的是，我们的研究表明，当使用微卫星或微卫星标记物时，肿瘤内克隆异质性可能会导致癌症活检标本分子诊断中的采样误差。
