Bomme L, Heim S, Bardi G, Fenger C, Kronborg O, Brøgger A, Lothe R A
Department of Medical Genetics, Odense University, Denmark.
Genes Chromosomes Cancer. 1998 Mar;21(3):185-94. doi: 10.1002/(sici)1098-2264(199803)21:3<185::aid-gcc2>3.0.co;2-w.
Both cytogenetic and molecular genetic analyses have shown that many colorectal adenomas carry an acquired deletion distally in the short arm of one chromosome 1, but the two methods have never been brought to bear on the same tumors. The major part of this study was the analysis of 53 previously short-term cultured and karyotyped colorectal adenomas for allelic imbalance at eight microsatellite loci in 1p. Allelic imbalances were detected in seven of the 12 adenomas that had cytogenetically visible abnormalities of chromosome 1, as well as in four adenomas that either had a normal karyotype (one case) or had clonal chromosome abnormalities that did not seem to involve chromosome 1 (three cases); i.e., 30% of the adenomas had abnormalities involving 1p by the combined approach. A minimal region of overlap seemed to map to between DIS199 and DIS234, suggesting that this is a relevant target region. This genomic area contains the human homologue of the tumor modifier gene Mom1 (1p35-36.1), which, in mice, modifies the number of intestinal tumors in multiple intestinal neoplasia (Min)-mutated animals. To evaluate whether the imbalances corresponded to interstitial deletions of 1p material, we performed fluorescence in situ hybridization with a pericentromeric probe (15 adenomas) and a telomeric probe (6 adenomas) on uncultured cells from the 16 adenomas with chromosome 1 abnormalities. Except for three adenomas that had already been shown by banding analysis to have a trisomic pattern, two centromere 1 signals were invariably found. In the cases hybridized with the 1p-telomeric probe, we found the same frequencies of telomeric and centromeric signals, in agreement with the interpretation that the deletions were interstitial. One of the 53 adenomas had genomic instability, seen as new alleles at five of eight microsatellite loci. A comparison of the genetic findings with clinicopathologic data indicated that adenomas in the rectum have 1p abnormalities more often than do adenomas of the sigmoid colon, and that adenomas with 1p changes are larger than adenomas without abnormalities of chromosome 1.
细胞遗传学和分子遗传学分析均表明，许多结直肠腺瘤在1号染色体短臂的远侧存在一个获得性缺失，但这两种方法从未应用于同一肿瘤。本研究的主要部分是对53例先前经过短期培养和核型分析的结直肠腺瘤进行分析，检测其1p上8个微卫星位点的等位基因失衡情况。在12例细胞遗传学上可见1号染色体异常的腺瘤中，有7例检测到等位基因失衡，在4例核型正常（1例）或克隆性染色体异常似乎不涉及1号染色体（3例）的腺瘤中也检测到等位基因失衡；即，通过联合方法，30%的腺瘤存在涉及1p的异常。一个最小重叠区域似乎定位于DIS199和DIS234之间，提示这是一个相关的靶区域。该基因组区域包含肿瘤修饰基因Mom1（1p35 - 36.1）的人类同源物，在小鼠中，该基因可改变多发性肠道肿瘤（Min）突变动物的肠道肿瘤数量。为评估这些失衡是否对应于1p物质的间质性缺失，我们对16例有1号染色体异常的腺瘤的未培养细胞进行了着丝粒探针（15例腺瘤）和端粒探针（6例腺瘤）的荧光原位杂交。除了3例已通过显带分析显示为三体模式的腺瘤外，总是发现两个1号着丝粒信号。在与1p端粒探针杂交的病例中，我们发现端粒和着丝粒信号的频率相同，这与缺失为间质性的解释一致。53例腺瘤中有1例存在基因组不稳定，表现为8个微卫星位点中的5个出现新的等位基因。将遗传结果与临床病理数据进行比较表明，直肠腺瘤比乙状结肠腺瘤更常出现1p异常，且有1p改变的腺瘤比无1号染色体异常的腺瘤更大。
