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Very frequent p53 mutations in metastatic prostate carcinoma and in matched primary tumors. 1998

F J Meyers, and P H Gumerlock, and S G Chi, and H Borchers, and A D Deitch, and R W deVere White
Department of Internal Medicine, the University of California-Davis, and the University of California-Davis Cancer Center, Sacramento 95817, USA.

BACKGROUND The frequency of mutant p53 in bone marrow metastases of patients with carcinoma of the prostate (CaP) and in matched sets of metastatic and primary lesions from the same patients was investigated. The data were examined in relation to prior treatment with androgen ablation (AA) therapy and were compared with the frequency of mutant p53 reported for primary CaP. METHODS Seventeen patients with M1b (bone metastasis: TNM Stage IV) CaP had either unilateral or bilateral bone marrow biopsies taken for these studies. Specimens were divided and the outer one-third examined histologically to confirm the presence of CaP cells. Immunohistochemical (IHC) staining for accumulated p53 protein was performed by an antibody cocktail technique. RNA was extracted from the remaining portion of the biopsy, and p53 transcripts were amplified by reverse transcriptase-polymerase chain reaction (RT-PCR) and screened for base sequence changes in the exon 4-11 region using nonisotopic single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing. RESULTS Ten of 17 metastases (59%) demonstrated accumulation of p53. Six of 7 (86%) of the p53 IHC positive bone marrow samples contained RT-PCR-SSCP abnormalities, as did 2 of 3 IHC negative samples. Overall, 12 of 17 metastases (71%) contained mutant p53. Four of 7 biopsies (57%) retrieved prior to AA contained mutant p53, whereas 8 of 10 post-AA biopsies (80%) contained mutant p53. One patient showed identical SSCP abnormalities in right and left iliac crest metastases after therapy, and in this patient DNA sequencing demonstrated a missense mutation at codon 126 (TAC --> GGC, Tyr --> Gly). Archival primary cancers from seven patients were retrieved. All seven were IHC positive for p53 accumulation. CONCLUSIONS p53 mutations are associated with increased metastatic potential of CaP. Abnormalities are found at approximately twice the frequency in metastases than in unselected samples of primary CaP, whereas in matched specimens there is a high rate of consonance. Mutant p53 may contribute to systemic therapy resistance, due to increased association with post-AA CaP specimens.

UI MeSH Term Description Entries
D008297 Male Males
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D009363 Neoplasm Proteins Proteins whose abnormal expression (gain or loss) are associated with the development, growth, or progression of NEOPLASMS. Some neoplasm proteins are tumor antigens (ANTIGENS, NEOPLASM), i.e. they induce an immune reaction to their tumor. Many neoplasm proteins have been characterized and are used as tumor markers (BIOMARKERS, TUMOR) when they are detectable in cells and body fluids as monitors for the presence or growth of tumors. Abnormal expression of ONCOGENE PROTEINS is involved in neoplastic transformation, whereas the loss of expression of TUMOR SUPPRESSOR PROTEINS is involved with the loss of growth control and progression of the neoplasm. Proteins, Neoplasm
D011471 Prostatic Neoplasms Tumors or cancer of the PROSTATE. Cancer of Prostate,Prostate Cancer,Cancer of the Prostate,Neoplasms, Prostate,Neoplasms, Prostatic,Prostate Neoplasms,Prostatic Cancer,Cancer, Prostate,Cancer, Prostatic,Cancers, Prostate,Cancers, Prostatic,Neoplasm, Prostate,Neoplasm, Prostatic,Prostate Cancers,Prostate Neoplasm,Prostatic Cancers,Prostatic Neoplasm
D001853 Bone Marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Marrow,Red Marrow,Yellow Marrow,Marrow, Bone,Marrow, Red,Marrow, Yellow
D001859 Bone Neoplasms Tumors or cancer located in bone tissue or specific BONES. Bone Cancer,Cancer of Bone,Cancer of the Bone,Neoplasms, Bone,Bone Neoplasm,Neoplasm, Bone
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D016133 Polymerase Chain Reaction In vitro method for producing large amounts of specific DNA or RNA fragments of defined length and sequence from small amounts of short oligonucleotide flanking sequences (primers). The essential steps include thermal denaturation of the double-stranded target molecules, annealing of the primers to their complementary sequences, and extension of the annealed primers by enzymatic synthesis with DNA polymerase. The reaction is efficient, specific, and extremely sensitive. Uses for the reaction include disease diagnosis, detection of difficult-to-isolate pathogens, mutation analysis, genetic testing, DNA sequencing, and analyzing evolutionary relationships. Anchored PCR,Inverse PCR,Nested PCR,PCR,Anchored Polymerase Chain Reaction,Inverse Polymerase Chain Reaction,Nested Polymerase Chain Reaction,PCR, Anchored,PCR, Inverse,PCR, Nested,Polymerase Chain Reactions,Reaction, Polymerase Chain,Reactions, Polymerase Chain
D016158 Genes, p53 Tumor suppressor genes located on the short arm of human chromosome 17 and coding for the phosphoprotein p53. Genes, TP53,TP53 Genes,p53 Genes,Gene, TP53,Gene, p53,TP53 Gene,p53 Gene

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