Loss of the tumor suppressor PML in human cancers of multiple histologic origins Journal Article
| Authors: | Gurrieri, C.; Capodieci, P.; Bernardi, R.; Scaglioni, P. P.; Nafa, K.; Rush, L. J.; Verbel, D. A.; Cordon-Cardo, C.; Pandolfi, P. P. |
| Article Title: | Loss of the tumor suppressor PML in human cancers of multiple histologic origins |
| Abstract: | Background: The PML gene is fused to the RARα 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. © Oxford University Press 2004, all rights reserved. |
| Keywords: | immunohistochemistry; controlled study; human tissue; protein expression; protein array analysis; gene mutation; human cell; major clinical study; mutation; cancer growth; solid tumor; cancer staging; lymph node metastasis; neoplasm staging; cancer grading; polymerase chain reaction; adenocarcinoma; protein analysis; gene expression; protein depletion; lung neoplasms; neoplasm proteins; colonic neoplasms; gene frequency; gene function; immunofluorescence; breast neoplasms; histology; central nervous system tumor; central nervous system neoplasms; carcinogenesis; transcription factors; nuclear proteins; adrenal cortex carcinoma; cancer invasion; prostatic neoplasms; in situ hybridization; fluorescent antibody technique; gene expression regulation, neoplastic; nonhodgkin lymphoma; statistical analysis; messenger rna; rna, messenger; breast carcinoma; tumor suppressor proteins; tumor cell line; promyelocytic leukemia; gene fusion; carcinoma; lung carcinoma; thyroid carcinoma; thyroid neoplasms; prostate adenocarcinoma; heterozygosity loss; dna primers; loss of heterozygosity; germ cell tumor; blotting, northern; colon adenocarcinoma; protein microarray; adrenal cortex neoplasms; northern blotting; promyelocytic leukemia protein; retinoic acid receptor alpha; germinoma; receptors, retinoic acid; humans; human; male; female; priority journal; article |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 96 |
| Issue: | 4 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2004-02-18 |
| Start Page: | 269 |
| End Page: | 279 |
| Language: | English |
| PROVIDER: | scopus |
| PUBMED: | 14970276 |
| DOI: | 10.1093/jnci/djh043 |
| DOI/URL: | |
| Notes: | J. Natl. Cancer Inst. -- Cited By (since 1996):168 -- Export Date: 16 June 2014 -- CODEN: JNCIA C2 - 14970276 -- Source: Scopus |
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