Molecular alterations associated with breast cancer mortality.

BACKGROUND: Breast cancer is a heterogeneous disease and patients with similar pathologies and treatments may have different clinical outcomes. Identification of molecular alterations associated with disease outcome may improve risk assessment and treatments for aggressive breast cancer. METHODS: Allelic imbalance (AI) data was generated for 122 invasive breast tumors with known clinical outcome. Levels and patterns of AI were compared between patients who died of disease (DOD) and those with ≥5 years disease-free survival (DFS) using Student t-test and chi-square analysis with a significance value of P<0.05. RESULTS: Levels of AI were significantly higher in tumors from the 31 DOD patients (28.6%) compared to the 91 DFS patients (20.1%). AI at chromosomes 7q31, 8p22, 13q14, 17p13.3, 17p13.1 and 22q12.3 was associated with DOD while AI at 16q22-q24 was associated with DFS. After multivariate analysis, AI at chromosome 8p22 remained an independent predictor of breast cancer mortality. The frequency of AI at chromosome 13q14 was significantly higher in patients who died ≥5 years compared to those who died <5 years from diagnosis. CONCLUSION: Tumors from DOD compared to DFS patients are marked by increased genomic instability and AI at chromosome 8p22 is significantly associated with breast cancer morality, independent of other clinicopathological factors. AI at chromosome 13q14 was associated with late (>5-years post-diagnosis) mortality but not with death from disease within five years, suggesting that patients with short- and long-term mortality may have distinct genetic diseases.

Potential clinical importance of the activation peptide of prostate-specific antigen.

Prostate cancer is the second leading cause of cancer death in men. Prostate specific antigen (PSA) is currently the best marker available for screening and monitoring disease recurrence, but its use has limitations. This study investigates the biosynthesis, secretion and activation of PSA in a prostate adenocarcinoma cell line. PSA is secreted as a pro-enzyme containing a seven amino acid activation peptide (APLILSR). Because the activation peptide is removed extracellularly in vivo, we hypothesized that it may be detected in the blood or urine. Activated PSA is a serine protease and reacts rapidly with protease inhibitors in the blood. These protein complexes are removed from the circulatory system by hepatocyte-mediated endocytosis. This rapid clearance likely interferes with detection of PSA in the early stages of prostate cancer. Notably these clearance mechanisms are not considered when PSA levels are determined clinically. We used radio-labeled proteins to determine the clearance of PSA in complex with its inhibitors as well as in vivo clearance of APLILSR. Dot blotting was used to determine the presence of APLILSR in human urine samples. Our data indicates that PSA-alpha1-antichymotrypsin only accumulates in the blood when large amounts of PSA are present and saturate clearance mechanisms. We found that APLILSR is filtered from the bloodstream by the kidney, and is detectable in the urine of patients with prostate cancer, but not controls. We propose that urine detection of the PSA activation peptide may represent a clinically sensitive measure of PSA production/secretion.

Thyroidectomies from patients with history of therapeutic radiation during childhood and adolescence have a unique mutational profile.

Radiation in childhood is a known risk factor for thyroid carcinoma, but may also be related to benign nodular hyperplasias. Recent evidence from comparative genomic hybridization indicates that radiation can induce clonal DNA damage in cultured rat thyrocytes. We used a loss of heterozygosity analysis for the loci identified by comparative genomic hybridization to study human thyroids. Thyroids from patients with a history of radiation, patients who had recent therapeutic external beam radiation for laryngeal carcinoma, and patients who had no radiation and underwent incidental thyroidectomy with laryngectomy for laryngeal carcinoma were included. PCR was performed for 18 different genetic loci defined by prior reported comparative genomic hybridization study. A semiquantitative capillary electrophoresis analysis was used and frequency of allelic loss was calculated from the number of losses/the number of informative loci. A total of 40 cases of thyroids from patients with childhood radiation, 12 cases of recently radiated thyroids, and 15 cases of nonradiated thyroids were included. In the nonradiated and recently radiated thyroids, the mean frequency of allelic loss was 2.3%. In the thyroids from patients radiated as children, the mean frequency of allelic loss was 39%. Losses were seen at every locus with a range of 7-100% of the cases analyzed (mean 49.6%). Radiation in childhood was associated with both benign nodular disease and carcinomas of the thyroid. The frequency of allelic loss was very high in all lesions in these patients, as compared to control thyroid glands. These data from human thyroids support prior cell culture experiments and show that radiation induces genetic mutational damage even in benign proliferative processes in these thyroids.