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Clonal origin of lymph node metastases in bladder carcinoma
Timothy D Jones1, Matthew D Carr, John N Eble
1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Cancer
|October 1, 2005
Summary
Multiple bladder cancer metastases often originate from a single tumor clone, suggesting metastasis capability arises early. Genetic analysis of urothelial carcinoma (UC) and its spread reveals clonal origins and evolutionary divergence.
Area of Science:
- Uro-oncology
- Cancer Genetics
- Molecular Pathology
Background:
- Genetic heterogeneity in urothelial carcinoma (UC) raises questions about the clonal origin of UC and its metastases.
- High-grade UC frequently metastasizes to regional lymph nodes, but the clonal origin of these metastases is uncertain.
- Molecular analysis can elucidate the genetic basis of UC progression and metastasis.
Purpose of the Study:
- To investigate the clonal origin of multiple lymph node metastases in urothelial carcinoma.
- To determine if lymph node metastases arise from the same or different tumor clones within the primary bladder cancer.
- To understand the genetic basis of urothelial carcinoma progression and metastasis through molecular analysis.
Main Methods:
- Analysis of 24 patients with urothelial carcinoma and multiple lymph node metastases.
- Laser-assisted microdissection of genomic DNA from primary tumors and lymph node metastases.
- Loss of heterozygosity (LOH) assays on chromosomes 9p21, 9q32, and 17p13 (TP53 locus).
- X-chromosome inactivation analysis in primary tumors and metastases from female patients.
Main Results:
- High frequency of allelic loss observed in both primary urothelial carcinomas (67%) and metastatic carcinomas (79%).
- Identical LOH patterns were found in the primary tumor and all lymph node metastases in 11 out of 24 tumors.
- Clonality analysis indicated a common clonal origin for primary tumors and metastases in 5 out of 9 informative cases.
- Variable LOH patterns and X-chromosome inactivation patterns were observed in a subset of tumors, suggesting genetic divergence.
Conclusions:
- Multiple lymph node metastases and primary urothelial carcinomas share the same clonal origin.
- The capability for metastasis likely arises from a single clonal population within the primary tumor.
- Observed genetic variations reflect clonal evolution and divergence during urothelial carcinoma progression.