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Evaluation of the clonal relationship between primary and metastatic renal cell carcinoma by comparative genomic
H Bissig1, J Richter, R Desper
1Institute of Pathology,* University of Basel, Basel, Switzerland National Institutes of Health, Bethesda, Maryland Heidelberg, Germany.
Abstract:
The outcome of patients with renal cell carcinoma is limited by the development of metastasis after nephrectomy. To evaluate the genetic basis underlying metastatic progression of human renal cell carcinoma in vivo, we performed a comparative genomic hybridization analysis in 32 clear-cell renal-cell carcinoma metastases. The most common losses involved chromosomes 3p (25%), 4q (28%), 6q (28%), 8p (31%), and 9p (47%). The most common gains were detected at 17q (31%) and Xq (28%). There was one high-level gene amplification at chromosome 11q22-23. The mean number of aberrations in lymph node (4.8 +/- 2.8) and lung metastases (6.2 +/- 4.0) was lower than in other hematogenous metastases (11.5 +/- 8.7, P < 0.05), suggesting that hematogenous dissemination is linked to an acquisition of complex genomic alterations. As genetic differences between primary tumors and metastases give information on genetic changes that have contributed to the metastatic process, relative DNA sequence copy number changes in 19 matched tumor pairs were compared. Genomic changes, which frequently occurred in metastases but not in the corresponding primary tumor were losses of 8p and 9p and gains of 17q and Xq. An abnormal function of genes in these regions may contribute to the metastatic process. According to a statistical analysis of shared genetic changes in matched tumor pairs, a high probability of a common clonal progenitor was found in 11 of 19 patients (58%). Six metastases (32%) were genetically almost completely different from the primary, suggesting that detection of genomic alterations in primary tumors gives only a restricted view of the biological properties of metastatic renal cell carcinoma.
Insights
Metastasis in renal cell carcinoma involves genetic changes. Comparative genomic hybridization revealed common chromosomal losses and gains in metastases, with hematogenous spread linked to complex genomic alterations, impacting treatment strategies.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Renal cell carcinoma (RCC) metastasis significantly limits patient outcomes post-nephrectomy.
- Understanding the genetic underpinnings of RCC metastasis is crucial for improving patient prognosis.
Purpose of the Study:
- To investigate the genetic basis of metastatic progression in human clear-cell renal cell carcinoma (ccRCC) using comparative genomic hybridization (CGH).
- To identify specific genomic alterations associated with metastasis and compare them between primary tumors and metastatic sites.
Main Methods:
- Comparative genomic hybridization (CGH) analysis was performed on 32 ccRCC metastases.
- Genomic alterations in 19 matched primary tumor-metastasis pairs were analyzed.
- Statistical analysis was used to assess shared genetic changes and clonal origins.
Main Results:
- Common chromosomal losses in metastases included 3p, 4q, 6q, 8p, and 9p; common gains included 17q and Xq.
- Lymph node and lung metastases showed fewer genomic aberrations than hematogenous metastases, suggesting a link between dissemination route and genomic complexity.
- Genomic changes frequently observed in metastases but not primary tumors were losses of 8p/9p and gains of 17q/Xq.
- Approximately 32% of metastases were genetically distinct from their primary tumors.
Conclusions:
- Specific genomic alterations, particularly losses of 8p/9p and gains of 17q/Xq, are associated with RCC metastasis.
- Hematogenous spread of ccRCC correlates with more complex genomic alterations.
- Analyzing primary tumors alone provides a limited view of metastatic ccRCC biology; understanding metastatic genetics is vital.