© 2004 by Oxford University Press
© 2004 Oxford University Press
ARTICLE |
Loss of the Tumor Suppressor PML in Human Cancers of Multiple Histologic Origins
Affiliations of authors: Molecular Biology Program and Department of Pathology (CG, RB, PPP), Department of Pathology (PC, CCC), Molecular Biology Program and Departments of Pathology and Medicine (PPS), Department of Medicine (KN), Department of Epidemiology and Biostatistics (DAV), Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, NY; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH (LJR).
Correspondence to: Pier Paolo Pandolfi, MD, PhD, Molecular Biology Program and Department of Pathology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Box 110, 1275 York Ave., New York, NY 10021 (e-mail: p-pandolfi{at}ski.mskcc.org)
Background: The PML gene is fused to the RAR
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.
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- Tissue Microarrays for Hypothesis Generation
- Ethan Dmitrovsky
J Natl Cancer Inst 2004 96: 248-249.[Extract] [Full Text] [PDF]
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