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Allelic imbalance and microsatellite instability in prostatic adenocarcinoma
J M Cunningham1, A Shan, M J Wick
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Abstract:
Although prostate cancer is one of the most common malignancies of males in Western countries, relatively little is known about the molecular mechanisms involved in tumor initiation and progression. Allelic loss studies have suggested the involvement of multiple tumor suppressor genes (TSGs), but few detailed studies of all chromosomes have been performed. In an effort to localize and identify candidate TSGs, we performed allelic imbalance (AI) studies on 55 prostate cancers, using 135 polymorphic microsatellite markers. For the entire chromosome. AI ranged from a low of 0% on chromosomes 14 and 20 to a high of 71% on chromosome 8. Chromosomal regions demonstrating at least twice the background frequency of AI (ranging from 20 to 69%) included 5q, 6q, 7q, 8p, 13, l6q, l8q, and 21. In addition, AI was examined for association with a number of clinicopathological parameters. AI on chromosomes 7 and 16 were each associated with greater age at diagnosis (P = 0.009 and 0.001, respectively), and AI on chromosomes 10, 16, and 18 was associated with aneuploidy/tetraploidy (P = 0.037, 0.013, and 0.054, respectively). Furthermore, AI on chromosome 5 was associated with a higher pathological stage (P = 0.021) and on chromosome 8 and 16 with a higher Gleason score (P = 0.027 and 0.041, respectively). No tumor exhibited a phenotype of widespread microsatellite instability. These results indicate that there likely exist multiple sites harboring candidate TSG in prostate cancer, some of which may have important clinical implications, and which argue against widespread microsatellite instability.
Insights
This study identified multiple locations on chromosomes associated with prostate cancer development and progression. These findings suggest potential new therapeutic targets for this common male malignancy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Prostate cancer is a common male malignancy with poorly understood molecular drivers.
- Allelic loss studies suggest multiple tumor suppressor genes (TSGs) are involved, but comprehensive analyses are limited.
Purpose of the Study:
- To localize and identify candidate TSGs in prostate cancer.
- To investigate the association of allelic imbalance (AI) with clinicopathological parameters.
Main Methods:
- Performed allelic imbalance (AI) studies on 55 prostate cancer samples using 135 polymorphic microsatellite markers.
- Analyzed AI across all chromosomes to identify regions with significant imbalance.
- Correlated AI with patient age, ploidy status, pathological stage, and Gleason score.
Main Results:
- Allelic imbalance varied significantly across chromosomes, with high frequencies on chromosomes 8, 5q, 6q, 7q, 8p, 13, 16q, 18q, and 21.
- AI on chromosomes 7 and 16 correlated with older age at diagnosis.
- AI on chromosomes 5, 8, and 16 associated with higher pathological stage and Gleason scores, respectively.
- AI on chromosomes 10, 16, and 18 linked to aneuploidy/tetraploidy.
Conclusions:
- Multiple chromosomal sites likely harbor TSGs crucial for prostate cancer initiation and progression.
- Specific AI patterns correlate with key clinical features, suggesting potential prognostic or therapeutic implications.
- The study argues against widespread microsatellite instability as a primary mechanism in prostate cancer.