Loss of the tumor suppressor PML in human cancers of multiple histologic origins

Carmela Gurrieri, Paola Capodieci, Rosa Bernardi, Pier Paolo Scaglioni, Khedoudja Nafa, Laura J. Rush, David A. Verbel, Carlos Cordon-Cardo, Pier Paolo Pandolfi

Research output: Contribution to journalArticle

252 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)269-279
Number of pages11
JournalJournal of the National Cancer Institute
Volume96
Issue number4
StatePublished - Feb 18 2004

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Confidence Intervals
Neoplasms
Central Nervous System Neoplasms
Adenocarcinoma
Tumor Cell Line
Carcinoma
Acute Promyelocytic Leukemia
Proteins
Loss of Heterozygosity
Germ Cell and Embryonal Neoplasms
Breast Neoplasms
Messenger RNA
Prostate
Colon
Prostatic Intraepithelial Neoplasia
Genes
Adrenocortical Carcinoma
Lung
Thyroid Neoplasms
Northern Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gurrieri, C., Capodieci, P., Bernardi, R., Scaglioni, P. P., Nafa, K., Rush, L. J., ... Pandolfi, P. P. (2004). Loss of the tumor suppressor PML in human cancers of multiple histologic origins. Journal of the National Cancer Institute, 96(4), 269-279.

Loss of the tumor suppressor PML in human cancers of multiple histologic origins. / Gurrieri, Carmela; Capodieci, Paola; Bernardi, Rosa; Scaglioni, Pier Paolo; Nafa, Khedoudja; Rush, Laura J.; Verbel, David A.; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo.

In: Journal of the National Cancer Institute, Vol. 96, No. 4, 18.02.2004, p. 269-279.

Research output: Contribution to journalArticle

Gurrieri, C, Capodieci, P, Bernardi, R, Scaglioni, PP, Nafa, K, Rush, LJ, Verbel, DA, Cordon-Cardo, C & Pandolfi, PP 2004, 'Loss of the tumor suppressor PML in human cancers of multiple histologic origins', Journal of the National Cancer Institute, vol. 96, no. 4, pp. 269-279.
Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ et al. Loss of the tumor suppressor PML in human cancers of multiple histologic origins. Journal of the National Cancer Institute. 2004 Feb 18;96(4):269-279.
Gurrieri, Carmela ; Capodieci, Paola ; Bernardi, Rosa ; Scaglioni, Pier Paolo ; Nafa, Khedoudja ; Rush, Laura J. ; Verbel, David A. ; Cordon-Cardo, Carlos ; Pandolfi, Pier Paolo. / Loss of the tumor suppressor PML in human cancers of multiple histologic origins. In: Journal of the National Cancer Institute. 2004 ; Vol. 96, No. 4. pp. 269-279.
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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.",
author = "Carmela Gurrieri and Paola Capodieci and Rosa Bernardi and Scaglioni, {Pier Paolo} and Khedoudja Nafa and Rush, {Laura J.} and Verbel, {David A.} and Carlos Cordon-Cardo and Pandolfi, {Pier Paolo}",
year = "2004",
month = "2",
day = "18",
language = "English (US)",
volume = "96",
pages = "269--279",
journal = "Journal of the National Cancer Institute",
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TY - JOUR

T1 - Loss of the tumor suppressor PML in human cancers of multiple histologic origins

AU - Gurrieri, Carmela

AU - Capodieci, Paola

AU - Bernardi, Rosa

AU - Scaglioni, Pier Paolo

AU - Nafa, Khedoudja

AU - Rush, Laura J.

AU - Verbel, David A.

AU - Cordon-Cardo, Carlos

AU - Pandolfi, Pier Paolo

PY - 2004/2/18

Y1 - 2004/2/18

N2 - 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.

AB - 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.

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