Velasco Alfredo, Riquelme Erick, Schultz Marcela, Wistuba Ignacio I, Villarroel Luis, Pizarro Javier, Berlin Alejandro, Ittmann Michael, Koh Moon S, Leach Fredrick S
Department of Urology, Catholic University of Chile, Santiago, Chile.
Cancer Biol Ther. 2004 Oct;3(10):977-82. doi: 10.4161/cbt.3.10.1135. Epub 2004 Oct 2.
Human mismatch repair (MMR) genes encode highly conserved interacting proteins that correct replication errors predisposing to hereditary gastrointestinal and genitourinary malignancies. A subset of sporadic genitourinary tumors also exhibits MMR deficiency and can be identified by measuring the frequency of microsatellite instability (MSI) in cancer cell DNA. We investigated expression of the two most commonly mutated MMR genes, MSH2 and MLH1, in sporadic testicular germ cell tumor (GCT) in order to: (1) determine the expression pattern of MSH2 and MLH1 proteins in normal seminiferous tubules and histologically distinct GCT subtypes, (2) correlate MMR gene expression with genetic instability in GCT and (3) develop a panel of molecular markers that can identify genetically distinct subsets of GCT for prognostic assessment. MSH2 and MLH1 had differential staining patterns in normal seminiferous tubules and malignant tissues. MSH2 was expressed in all stages of spermatogenesis up to but excluding mature sperm whereas MLH1 was predominantly expressed in premeiotic germ cells. All histological GCT subtypes showed differential immunostaining for MSH2 and MLH1 however pure seminoma had statistically significant fewer low MSH2 staining tumors than other subtypes (p = 0.046). Twenty-five percent of GCT exhibited increased frequency of MSI (MSI+ tumors) with 73, 70 and 43% of MSI+ tumors exhibiting low MSH2, low MLH1 or low MSH2 and low MLH1 staining respectively. Fifteen percent of testicular GCT exhibited loss of heterozygosity (LOH) but no MSI (LOH only tumors). Only 28, 17 or 6% of LOH only tumors exhibited low MSH2, low MLH1 or low MSH2 and low MLH1 staining respectively.
人类错配修复（MMR）基因编码高度保守的相互作用蛋白，这些蛋白可纠正易导致遗传性胃肠道和泌尿生殖系统恶性肿瘤的复制错误。一部分散发性泌尿生殖系统肿瘤也表现出MMR缺陷，可通过测量癌细胞DNA中的微卫星不稳定性（MSI）频率来识别。我们研究了散发性睾丸生殖细胞肿瘤（GCT）中两个最常发生突变的MMR基因MSH2和MLH1的表达情况，目的是：（1）确定MSH2和MLH1蛋白在正常生精小管和组织学上不同的GCT亚型中的表达模式，（2）将MMR基因表达与GCT中的基因不稳定性相关联，（3）开发一组分子标记物，可识别GCT的基因不同亚组以进行预后评估。MSH2和MLH1在正常生精小管和恶性组织中的染色模式不同。MSH2在精子发生的所有阶段均有表达，直至但不包括成熟精子，而MLH1主要在减数分裂前的生殖细胞中表达。所有组织学GCT亚型对MSH2和MLH1均表现出不同的免疫染色，然而，纯精原细胞瘤中低MSH2染色肿瘤的数量在统计学上显著少于其他亚型（p = 0.046）。25%的GCT表现出MSI频率增加（MSI+肿瘤），其中73%、70%和43%的MSI+肿瘤分别表现为低MSH2、低MLH1或低MSH2和低MLH1染色。15%的睾丸GCT表现出杂合性缺失（LOH）但无MSI（仅LOH肿瘤）。仅28%、17%或6%的仅LOH肿瘤分别表现为低MSH2、低MLH1或低MSH2和低MLH1染色。
