Hessman O, Skogseid B, Westin G, Akerström G
Department of Surgical Sciences, Endocrine Unit, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
J Clin Endocrinol Metab. 2001 Mar;86(3):1355-61. doi: 10.1210/jcem.86.3.7332.
Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome with multiple tumors of the endocrine pancreas, the parathyroid, the pituitary, and other tissues. The MEN1 gene at 11q13 is homozygously mutated in the majority of MEN1 tumors. Here we present a genome-wide loss of heterozygosity (LOH) screening of 23 pancreatic lesions, one duodenal tumor, and one thymic carcinoid from 13 MEN1 patients. Multiple allelic deletions were found. Fractional allelic loss varied from 6-75%, mean 31%. All pancreatic tumors displayed LOH on chromosome 11, whereas the frequency of losses for chromosomes 3, 6, 8, 10, 18, and 21 was over 30%. Different lesions from individual patients had discrepant patterns of LOH. Intratumoral heterogeneity was revealed, with chromosome 6 and 11 deletions in most tumor cells, whereas other chromosomal loci were deleted in portions of the analyzed tumor. Chromosome 6 deletions were mainly found in lesions from patients with malignant features. Fractional allelic loss did not correlate to malignancy or to tumor size. Our findings indicate that MEN1 pancreatic tumors fail to maintain DNA integrity and demonstrate signs of chromosomal instability.
多发性内分泌腺瘤1型（MEN1）是一种遗传性综合征，在内分泌胰腺、甲状旁腺、垂体及其他组织中会出现多个肿瘤。11q13处的MEN1基因在大多数MEN1肿瘤中发生纯合突变。在此，我们对13例MEN1患者的23个胰腺病变、1个十二指肠肿瘤和1个胸腺类癌进行了全基因组杂合性缺失（LOH）筛查。发现了多个等位基因缺失。等位基因缺失率在6%至75%之间，平均为31%。所有胰腺肿瘤在11号染色体上均显示杂合性缺失，而3号、6号、8号、10号、18号和21号染色体的缺失频率超过30%。个体患者的不同病变具有不同的杂合性缺失模式。揭示了肿瘤内的异质性，大多数肿瘤细胞中6号和11号染色体缺失，而在部分分析的肿瘤中其他染色体位点缺失。6号染色体缺失主要见于具有恶性特征患者的病变中。等位基因缺失率与恶性程度或肿瘤大小无关。我们的研究结果表明，MEN1胰腺肿瘤无法维持DNA完整性，并表现出染色体不稳定的迹象。
