Loss of the tumor suppressor PML in human cancers of multiple histologic origins
Loss of the tumor suppressor PML in human cancers of multiple histologic origins
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DOI：
10.1093/jnci/djh043
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发表时间：
2004-02-18
影响因子：
10.3
通讯作者：
Pandoli, PP
中科院分区：
文献类型：
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作者：
Gurrieri, C;Capodieci, P;Pandoli, PP
背景：在绝大多数急性早幼粒细胞白血病(APL)中，PML基因与RARpha基因融合，并参与控制关键的肿瘤抑制途径。然而，它在除APL以外的人类癌症的发病机制中的作用仍不清楚。因此，我们评估了PML基因在多种组织来源的实体瘤中的状态和表达。方法：收集结肠腺癌(n=109)、肺癌(n=19)、前列腺癌(n=36)、乳腺癌(n=38)、中枢神经系统肿瘤(n=51)、生殖细胞肿瘤(n=60)、甲状腺癌(n=32)、肾上腺皮质癌(n=12)、非霍奇金淋巴瘤(n=251)和正常组织(n=251)的肿瘤组织芯片，分别用免疫组织化学和原位杂交法分析PML蛋白和mRNA的表达。用免疫荧光法和Northern印迹法分别检测不同组织来源的肿瘤细胞系()PML蛋白和mR NA的表达。对显微解剖的肿瘤样本和细胞系的DNA进行PML突变和杂合性丢失(LOH)分析。对于某些肿瘤类型，分析PML表达与肿瘤分期和分级的关系。统计检验是两面性的。结果：所有正常组织均表达PML蛋白。PML蛋白在前列腺癌(63%[95%可信区间=48%~78%]和28%[95%可信区间=13%~43%])、结肠腺癌(31%[95%可信区间=22%~40%]和17%[95%可信区间=10%~24%])、乳腺癌(21%[95%可信区间=8%~34%]和31%[95%可信区间=16%~46%])，肺癌(36%[95%CI=15%~57%]和21%[95%=3%~39%])，淋巴瘤(14%[95%CI=10%~18%]和69%[95%CI=63%~75%])，中枢神经系统肿瘤(24%[95%CI=13%~35%]和49%[95%CI=36%~62%])，生殖细胞肿瘤(36%[95%CI=24%~48%]和48%[95%CI=36%~60%])，甲状腺或肾上腺癌未见。PML蛋白表达缺失与前列腺癌(从前列腺上皮内瘤变到浸润性癌的进展与PML完全缺失相关；P<；.001)、乳腺癌(完全PML缺失与淋巴结转移相关；P=.01)和中枢神经系统肿瘤(完全PML缺失与高级别肿瘤相关；P=.003)的进展相关。所有肿瘤和细胞系标本均有PML mRNA表达。PML基因很少发生突变，不会发生杂合性缺失。结论：PML蛋白在不同组织来源的肿瘤中表达缺失，其缺失与某些肿瘤组织类型的肿瘤分级和进展有关。
Background: The PML gene is fused to the RARalpha gene in the vast majority of acute promyelocytic leukemias (APL) and has been implicated in the control of key tumor-suppressive pathways. However, its role in the pathogenesis of human cancers other than APL is still unclear. We therefore assessed the status and expression of the PML gene in solid tumors of multiple histologic origins. Methods: We created tumor tissue microarrays (TTMs) with samples from patients with colon adenocarcinoma (n = 109), lung carcinoma (n = 19), prostate adenocarcinoma (n = 36), breast carcinoma (n = 38), central nervous system (CNS) tumors (n = 51), germ cell tumors (n = 60), thyroid carcinoma (n = 32), adrenal cortical carcinoma (n = 12), and non-Hodgkin's lymphoma (n = 251) and from normal tissue corresponding to each histotype and analyzed PML protein and mRNA expression by immunohistochemistry and in situ hybridization, respectively. Tumor cell lines (n = 64) of various histologic origins were analyzed for PML protein and mRNA expression by immunofluorescence and northern blotting, respectively. DNA from microdissected tumor samples and cell lines was analyzed for PML mutations and loss of heterozygosity (LOH). For some tumor types, the association between PML expression and tumor stage and grade was analyzed. Statistical tests were two-sided. Results: All normal tissues expressed PML protein. PML protein expression was reduced or abolished in prostate adenocarcinomas (63% (95% confidence interval (CI) = 48% to 78%] and 28% [95% CI = 13% to 43%], respectively), colon adenocarcinomas (31% [95% CI = 22-% to 40%] and 17% [95% CI = 10% to 24%]), breast carcinomas (21% [95% CI = 8% to 34%] and 31% [95% CI = 16% to 46%]), lung carcinomas (36% [95% CI = 15% to 57%] and 21% [95% = 3% to 39%]), lymphomas (14% [95% CI = 10% to 18%] and 69% [95% CI = 63% to 75%]), CNS tumors (24% [95% CI = 13% to 35%] and 49% [95% CI = 36% to 62%]), and germ cell tumors (36% [95% CI = 24% to 48%] and 48% [95% CI = 36% to 60%]) but not in thyroid or adrenal carcinomas. Loss of PML protein expression was associated with tumor progression in prostate cancer (the progression from prostatic intraepithelial neoplasia to invasive carcinoma was associated with complete PML loss; P < .001), breast cancer (complete PML loss was associated with lymph node metastasis; P = .01), and CNS tumors (complete PML loss was associated with high-grade tumors; P = .003). PML mRNA was expressed in all tumor and cell line samples. The PML gene was rarely mutated and was not subject to LOH. Conclusions: PML protein expression is frequently lost in human cancers of various histologic origins, and its loss associates with tumor grade and progression in some tumor histotypes.