ARTICLES Loss of the Tumor Suppressor PML in Human Cancers of Multiple Histologic Origins

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 as-sessed 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 pa-tients with colon adenocarcinoma (n 109), lung carcinoma (n 19), prostate adenocarcinoma (n 36), breast carci-noma (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 hybridiza-tion, respectively. Tumor cell lines (n 64) of various his-tologic 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 het-erozygosity (LOH). For some tumor types, the association between PML expression and tumor stage and grade was analyzed. Statistical tests were two-sided. Results: All nor-mal 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 adenocarci-nomas (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 carcinoma