Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss
Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss
复制标题
DOI：
10.1158/0008-5472.can-03-2756
复制
发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Kern, SE
中科院分区：
文献类型：
--
作者：
Iacobuzio-Donahue, CA;van der Heijden, MS;Kern, SE
对人类癌症等位基因型的研究为了解肿瘤发生过程中基因失活的染色体提供了宝贵的见解。我们使用 386 个微卫星标记呈现 82 种异种移植胰腺癌或胆道癌的综合等位基因型，并以平均覆盖度 10 cM 跨越整个基因组。等位基因丢失在整个基因组中非随机分布，最常见于染色体臂 9p、17p 和 18q (>60%)，这些是已知肿瘤抑制基因 CDKN2A、TP53 和 MADH4 的位点。染色体臂 3p、6q、8p、17q、18p、21q 和 22q (40-60%) 出现中等程度的丢失率（在任何一个基因座）。等位基因丢失的各个位点的图谱显示，除了已知抑癌基因附近的位点外，还有 11 个杂合性丢失（>30%）的“热点”，对应于 3p、4q、5q、6q、8p、12q、14q、21q、22q 和 X 染色体。 82 种异种移植癌症的所有测试标记物的平均基因组分数等位基因丢失为 15.3%，等位基因丢失影响的测试位点少至 1.5%，多至 32.1%，范围达 20 倍之多。我们根据国家生物技术信息中心提供的绘图数据确定了所使用的 386 个标记中每一个的染色体位置（以 cM 为单位），并且我们首次提供了对人类上皮癌中丢失的染色体物质的基于距离的估计。具体来说，我们发现等位基因损失的累积大小范围为 58 至 1160 cM，平均损失为 561.32 cM/肿瘤。我们将每种异种移植癌症的基因组等位基因丢失分数与每位患者已知的临床病理学特征进行了比较，发现与吸烟状况显着相关（P < 0.01）。这些发现为研究胰胆癌常见的遗传改变提供了新的位点，并有助于了解人类致癌过程中等位基因丢失的机制。
Studies of the allelotype of human cancers have provided valuable insights into those chromosomes targeted for genetic inactivation during tumorigenesis. We present the comprehensive allelotype of 82 xenografted pancreatic or biliary cancers using 386 microsatellite markers and spanning the entire genome at an average coverage of 10 cM. Allelic losses were nonrandomly distributed across the genome and most prevalent for chromosome arms 9p, 17p, and 18q (>60%), sites of the known tumor suppressor genes CDKN2A, TP53, and MADH4. Moderate rates of loss (at any one locus) were noted for chromosome arms 3p, 6q, 8p, 17q, 18p, 21q, and 22q (40-60%). A mapping of individual loci of allelic loss revealed 11 "hot spots" of loss of heterozygosity (>30%) in addition to loci near known tumor suppressor genes, corresponding to 3p, 4q, 5q, 6q, 8p, 12q, 14q, 21q, 22q, and the X chromosome. The average genomic fractional allelic loss was 15.3% of all tested markers for the 82 xenografted cancers, with allelic loss affecting as little as 1.5% to as much as 32.1% of tested loci, a remarkable 20-fold range. We determined the chromosome location (in cM) of each of the 386 markers used based on mapping data available from the National Center for Biotechnology Information, and we provide the first distance-based estimates of chromosome material lost in a human epithelial cancer. Specifically, we found that the cumulative size of allelic losses ranged from 58 to 1160 cM, with an average loss of 561.32 cM/tumor. We compared the genomic fractional allelic loss of each xenografted cancer with known clinicopathological features for each patient and found a significant correlation with smoking status (P < 0.01). These findings offer new loci for investigation of the genetic alterations common to pancreaticobiliary cancers and aid the understanding of mechanisms of allelic loss in human carcinogenesis.