Poley Jan-Werner, Wagner Anja, Hoogmans Monique M C P, Menko Fred H, Tops Carli, Kros Johan M, Reddingius Roel E, Meijers-Heijboer Hanne, Kuipers Ernst J, Dinjens Winand N M
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Cancer. 2007 Jun 1;109(11):2349-56. doi: 10.1002/cncr.22697.
Heterozygous defects in mismatch-repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC). In this syndrome, tumors typically arise from age 25 years onward. Case reports have shown that homozygosity or compound heterozygosity for MMR gene mutations can cause multiple tumors in childhood, sometimes combined with neurofibromatosis type I (NF1)-like features. Therefore, the authors studied the role of homozygosity or compound heterozygosity (CZ) for MMR gene defects in children with multiple primary tumors.
A database that contained all pediatric oncology patients who were seen between 1982 and 2003 at the author's institution was queried to identify patients aged <16 years with more than 1 tumor for whom tissue of at least 1 tumor was available. On isolated DNA, microsatellite instability (MSI) and immunohistochemistry of MMR proteins were assessed.
In total, 15 patients with more than 1 tumor were identified. Abnormal test results were obtained in 2 of them, including 1 patient who was diagnosed at age 4 years with a glioblastoma (MSI-stable; no human mutL homolog 1 [MLH1] or postmeiotic segregation increased, Saccharomyces cerevisiae 2 [PMS2] expression) and a Wilms tumor (high MSI; no MLH1 or PMS2 expression). Apart from >6 cafe-au-lait spots, he had no other signs of NF1. The patient had CZ identified for a pathogenic MLH1 mutation (593delAG frameshift) and an unclassified MLH1 variant (Met35Asn). There was strong evidence that this unclassified variant was a pathogenic mutation. The second patient was diagnosed with a non-Hodgkin lymphoma (no tissue available) and an anaplastic oligodendroglioma (low MSI; no MSH6 expression) at age 4 years and 6 years, respectively. His brother had died of a medulloblastoma at age 6 years (low MSI, no MSH6 expression). Both boys had cafe-au-lait spots. Further genetic testing was not possible.
Carriage of biallelic MMR gene defects can be associated with multiple malignancies in childhood that may differ from the standard spectrum of HNPCC tumor types. In 15 pediatric patients with multiple malignancies, the authors identified 1 clear case and 1 possible case of biallelic MMR gene defect. Recognition of the inherited nature of the tumors in these patients is important for counseling these patients and their families.
错配修复（MMR）基因的杂合缺陷会导致遗传性非息肉病性结直肠癌（HNPCC）。在这种综合征中，肿瘤通常从25岁起发病。病例报告显示，MMR基因突变的纯合性或复合杂合性可导致儿童期出现多种肿瘤，有时还伴有I型神经纤维瘤病（NF1）样特征。因此，作者研究了MMR基因缺陷的纯合性或复合杂合性（CZ）在患有多种原发性肿瘤的儿童中的作用。
查询一个包含1982年至2003年在作者所在机构就诊的所有儿科肿瘤患者的数据库，以识别年龄小于16岁、患有1种以上肿瘤且至少有1种肿瘤组织可用的患者。对分离出的DNA进行微卫星不稳定性（MSI）评估和MMR蛋白的免疫组织化学检测。
总共识别出15例患有1种以上肿瘤的患者。其中2例检测结果异常，包括1例4岁时被诊断为胶质母细胞瘤的患者（MSI稳定；无人类mutL同源蛋白1 [MLH1]或减数分裂后分离增加，酿酒酵母2 [PMS2]表达）和1例肾母细胞瘤（高MSI；无MLH1或PMS2表达）。除了6个以上的咖啡牛奶斑外，他没有其他NF1的体征。该患者被鉴定为存在致病性MLH1突变（593delAG移码突变）和一个未分类的MLH1变异体（Met35Asn）的复合杂合性。有强有力的证据表明这个未分类的变异体是一个致病突变。第二名患者分别在4岁和6岁时被诊断为非霍奇金淋巴瘤（无可用组织）和间变性少突胶质细胞瘤（低MSI；无MSH6表达）。他的哥哥在6岁时死于髓母细胞瘤（低MSI，无MSH6表达）。两个男孩都有咖啡牛奶斑。无法进行进一步的基因检测。
双等位基因MMR基因缺陷可能与儿童期多种恶性肿瘤相关，这些肿瘤可能与HNPCC肿瘤类型的标准谱不同。在15例患有多种恶性肿瘤的儿科患者中，作者识别出1例明确的双等位基因MMR基因缺陷病例和1例可能的病例。认识到这些患者肿瘤的遗传性质对于为这些患者及其家人提供咨询很重要。
