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• W2040155712 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. 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. Prognosis of patients with renal cell carcinoma (RCC) is limited by the development of metastases. Five-year survival rates range from 50% to 85% in patients with organ-confined renal cancer (stage I and stage II). In contrast, less than one-third of patients with regional lymph node metastases survive 5 years. All but 5% to 10% of those patients with hematogenous metastases die within 5 years after diagnosis.1Robson C Churchill B Anderson W The results of radical nephrectomy for renal cell carcinoma.J Urol. 1969; 101: 297-303Abstract Full Text PDF PubMed Scopus (1216) Google Scholar The most common sites of distant metastasis are lung, liver, and bones, but metastases can also develop at any other site. The metastatic behavior of RCC is often bizarre and unpredictable2Weiss L Harlos JP Torhorst J Gunthard B Hartveit F Svendsen E Huang WL Grundmann E Eder M Zwicknagl M Metastatic patterns of renal carcinoma: an analysis of 687 necropsies.J Cancer Res Clin Oncol. 1988; 114: 605-612Crossref PubMed Scopus (121) Google Scholar, 3Bennington J Beckwith J Tumors of the Kidney, Renal Pelvis and Ureter. Armed Forces Institute of Pathology, Washington, DC1975Google Scholar, 4Johnsen JA Hellsten S Lymphatogenous spread of renal cell carcinoma: an autopsy study.J Urol. 1997; 157: 450-453Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar. Radiotherapy, chemotherapy, or hormonal therapy have little or no effect on metastatic RCC. Gene therapy with retroviral vector-mediated lymphokine gene transfer gave promising results in preclinical studies and is under further investigation.5Gastl G Finstad CL Guarini A Bosl G Gilboa E Bander NH Gansbacher B Retroviral vector-mediated lymphokine gene transfer into human renal cancer cells.Cancer Res. 1992; 52: 6229-6236PubMed Google Scholar The metastatic cells represent the prime targets of cancer therapy. However, little is known about genetic changes with importance for the development of RCC metastases.6Trent JM Stanisic T Olson S Cytogenetic analysis of urologic malignancies: study of tumor colony forming cells and premature chromosome condensation.J Urol. 1984; 131: 146-151PubMed Google Scholar, 7Sato M Hattori T Nishimura T Akimoto M Characterization of primary and metastatic cell lines established from a patient with renal cell carcinoma.Nippon Hinyokika Gakkai Zasshi. 1993; 84: 650-655PubMed Google Scholar, 8Peier AM Meloni AM Sandberg AA Leong SP Carroll PR Cytogenetic findings in a metastatic renal cell carcinoma.Cancer Genet Cytogenet. 1995; 80: 168-169Abstract Full Text PDF PubMed Scopus (3) Google Scholar, 9Gronwald J Störkel S Holtgreve-Grez H Hadaczek P Brinkschmidt C Jauch A Lubinski J Cremer T Comparison of DNA gains and losses in primary renal clear cell carcinomas and metastatic sites: importance of 1q and 3p copy number changes in metastatic events.Cancer Res. 1997; 57: 481-487PubMed Google Scholar Chromosome 9p losses in primary RCC were associated with short metastasis-free survival.10Moch H Presti Jr, JC Sauter G Buchholz N Jordan P Mihatsch MJ Waldman FM Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma.Cancer Res. 1996; 56: 27-30PubMed Google Scholar, 11Kinoshita H Yamada H Ogawa O Kakehi Y Osaka M Nakamura E Mishina M Habuchi T Takahashi R Sugiyama T Yoshida O Contribution of chromosome 9p21–22 deletion to the progression of human renal cell carcinoma.Jpn J Cancer Res. 1995; 86: 795-799Crossref PubMed Scopus (33) Google Scholar Expression of the epidermal growth factor receptor gene12Uhlman D Nguyen P Manivel J Zhang G Hagen K Fraley E Aeppä D Niehans G Epidermal growth factor receptor and transforming growth factor α expression in papillary and nonpapillary renal cell carcinoma: correlation with metastatic behavior and prognosis.Clin Cancer Res. 1995; 1: 913-920PubMed Google Scholar and the p53 gene13Uhlman D Nguyen P Manivel J Aeppli D Resnick J Fraley E Zhang G Niehans G Association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma.J Natl Cancer Inst. 1994; 86: 21470-147524Crossref Scopus (93) Google Scholar were associated with metastatic disease. Cancer is a genetically heterogeneous disease. Multiple clones of malignant cells are frequently detected by standard cytogenetics, by fluorescence in situ hybridization (FISH), and by flow cytometry.14Sauter G Moch H Gasser T Mihatsch M Waldman F Heterogeneity of chromosome 17 and erbB-2 gene copy number in primary and metastatic bladder cancer.Cytometry. 1995; 21: 40-46Crossref PubMed Scopus (34) Google Scholar, 15Pandis N Heim S Bardi G Idvall I Mandahl N Mitelman F Chromosome analysis of 20 breast carcinomas: cytogenetic multiclonality and karyotypic-pathologic correlations.Genes Chromosomes & Cancer. 1993; 6: 51-57Crossref PubMed Scopus (77) Google Scholar, 16Kallioniemi OP Comparison of fresh and paraffin-embedded tissue as starting material for DNA flow cytometry and evaluation of intratumor heterogeneity.Cytometry. 1988; 9: 164-169Crossref PubMed Scopus (222) Google Scholar, 17Trent J Yang JM Emerson J Dalton W McGee D Massey K Thompson F Villar H Clonal chromosome abnormalities in human breast carcinomas. II. Thirty-four cases with metastatic disease.Genes Chromosomes & Cancer. 1993; 7: 194-203Crossref PubMed Scopus (71) Google Scholar Animal studies suggest that the metastatic proportions of different cell clones may be related to the metastatic process.18Waghorne C Thomas M Lagarde A Genetic evidence for progressive selection and overgrowth of primary tumors by metastatic cell subpopulations.Cancer Res. 1988; 48: 6109-6114PubMed Google Scholar, 19Bell C Frost P Kerbel R Cytogenetic heterogeneity of genetically marked and metastatically competent “dominant” tumor cell clones.Cancer Genet Cytogenet. 1991; 54: 153-161Abstract Full Text PDF PubMed Scopus (22) Google Scholar Therefore, chromosomal alterations responsible for metastasis may be present only in cell subpopulations of the primary tumor, which may not be detectable by molecular analyses. However, chromosomal alterations with relevance for the metastatic process should be enriched in tissue samples from metastases. Analyzing genetic changes in the metastases rather than in the more commonly targeted primary tumors could shed new light onto the molecular mechanisms of the metastatic process. Studies comparing chromosomal changes in metastases with those found in the corresponding primary tumors in the same patient would be informative in revealing differences between primary and metastatic lesions and thereby pinpointing genetic events that could have predisposed to metastatic dissemination. Very little is known about genetic changes present in RCC metastases. Given the fact that RCC metastases may develop years or even decades after the removal of the primary tumor, genetic evolution certainly takes place within metastases. Analysis of primary tumors and their corresponding metastases allows one to assess the extent to which primary and metastatic cell clones are different from one another. A recently developed mathematical model allows testing of the statistical probability of a common clonal progenitor in primary tumors and their metastases.20Kuukasjärvi T Karhu R Tanner M Kähkönen M Schäffer A Nupponen N Pennanen S Kallioniemi A Kallioniemi O Isola J Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer.Cancer Res. 1997; 57: 1597-1604PubMed Google Scholar To search for cytogenetic events related to metastases, 32 RCC metastases and 19 corresponding primary tumors were screened by comparative genomic hybridization (CGH). CGH allows the detection of all clonal DNA-sequence copy number aberrations (>10 MB) across the entire genome.21Kallioniemi A Kallioniemi O Sudar D Rutovitz D Gray J Waldman F Pinkel D Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors.Science. 1992; 258: 818-821Crossref PubMed Scopus (2832) Google Scholar The results implicated several genomic regions that might carry genes involved in metastasis. The tumor specimens were obtained from the archives of the Institute for Pathology, University Basel. Twenty-seven patients with metastatic RCC were selected for this study according to the following criteria: 1) histologically representative metastatic specimens containing at least 75% tumor cells and having no necrosis were available, 2) the primary tumor was a histologically proven clear-cell RCC, and 3) the patient had not received any chemotherapy or radiotherapy before the diagnosis of metastases. Tissue was obtained from surgically resected metastases (n = 17) and from autopsies (n = 15). The anatomical distribution of metastatic sites was as follows: lymph node (n = 6), lung (n = 13), pancreas (n = 2), liver (n = 1), bone (n = 2), brain (n = 3), pelvis or abdominal cavity (n = 2), and soft tissue (n = 2). Tissue of different metastatic sites was obtained in three patients. Tissue of the corresponding primary tumor was available in 19 patients. Tumor DNA was extracted from 8 frozen and 24 formalin-fixed and paraffin-embedded metastases and from 8 frozen and 11 formalin-fixed and paraffin-embedded primary tumors. Specimens were trimmed to ensure a minimum of 75% tumor cells in the sample. Tissue preparation and DNA extraction was as described.22Richter J Jiang F Görög J Sartorius G Egenter C Gasser T Moch H Mihatsch M Sauter G Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization.Cancer Res. 1997; 57: 2860-2864PubMed Google Scholar, 23Jiang F Richter J Schraml P Bubendorf L Gasser T Mihatsch M Sauter G Moch H Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes.Am J Pathol. 1998; 153: 1467-1473Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar One microgram of tumor DNA was nick translated by using a commercial kit (BioNick kit, Life Technologies, Gaithersburg, MD) and Spectrum Green-dUTPs (Vysis, Downers Grove, IL) for direct labeling of tumor DNA. Spectrum-Red-labeled normal reference DNA (Vysis) was used for co-hybridization. The hybridization mixture consisted of 200 ng of Spectrum-Green-labeled tumor DNA, 200 ng of Spectrum-Red-labeled normal reference DNA, and 20 μg of Cot-1 DNA (GIBCO, Gaithersburg, MD. dissolved in 10 μl of hybridization buffer (50% formamide, 10. dextran sulfate, 2X SSC, pH 7.0). Hybridization, image acquisition, image analysis, and control experiments were exactly as described.22Richter J Jiang F Görög J Sartorius G Egenter C Gasser T Moch H Mihatsch M Sauter G Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization.Cancer Res. 1997; 57: 2860-2864PubMed Google Scholar, 23Jiang F Richter J Schraml P Bubendorf L Gasser T Mihatsch M Sauter G Moch H Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes.Am J Pathol. 1998; 153: 1467-1473Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar At least four observations per autosome and two observations per sex chromosome were included in each analysis. Each CGH experiment included a tumor cell line (Spectrum Green MPE-600, Vysis) with known aberrations (positive control) and a hybridization of two differentially labeled sex mismatched normal DNAs to each other (negative control). A gain of DNA sequences was assumed at chromosomal regions where the hybridization resulted in a tumor to normal ratio >1.20. Over-representations were considered amplifications when the fluorescence ratio values exceeded 1.5 in a subregion of a chromosome arm. A loss of DNA sequences was presumed where the tumor-to-normal ratio was <0.80. To define an aberration it was additionally required that the first SD was above (gain) or below (deletion) 1.00. As some false aberrations were detected in normal tissues at 1p, 16p, 19, and 22, these G-C-rich regions, known to produce false positive results by CGH, were excluded from all analyses.24Kallioniemi O Kallioniemi A Piper J Isola J Waldman F Gray J Pinkel D Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors.Genes Chromosomes & Cancer. 1994; 10: 231-243Crossref PubMed Scopus (944) Google Scholar The von Hippel-Lindau gene (VHL) on chromosome 3p25.5 is the strongest tumor suppressor gene candidate in RCC because somatic VHL gene mutations are present in ∼50% of RCCs25Gnarra JR Tory K Weng Y Schmidt L Wei MH Li H Latif F Liu S Chen F Duh FM Lubensky I Duan DR Florence C Pozzatti R Walther MM Bander NH Grossman HB Brauch H Pomer S Brooks JD Isaacs WB Lerman MI Zbar B Linehan WM Mutations of the VHL tumour suppressor gene in renal carcinoma.Nat Genet. 1994; 7: 85-90Crossref PubMed Scopus (1518) Google Scholar with 3p losses. Microsatellite analysis was used to detect VHL deletion in primary tumors and its metastases from 18 patients, where normal tissue was also available. The same tumor DNA specimens were used for CGH and microsatellite analysis. Normal DNA, extracted either from surrounding normal tissue or from liver tissue obtained at autopsy, was used in the loss of heterozygosity (LOH) analysis. LOH analysis was performed using the polymorphic microsatellite markers D3S135026Li H Schmidt L Wei MH Hustad T Lerman MI Zbar B Tory K Three tetrameric repeat polymorphisms on human chromosome 3: D3S1349; D3S1350; D3S1351.Hum Mol Genet. 1993; 2: 819Crossref PubMed Scopus (6) Google Scholar and D3S1038,27Crossey PA Maher ER Jones MH Richards FM Latif F Phipps ME Lush M Foster K Tory K Green JS Oostra B Yates JRW Linehan WM Affara NA Lerman M Zbar B Nakamura Y Ferguson-Smith MA Genetic linkage between von Hippel-Lindau disease and three microsatellite polymorphisms refines the localisation of the VHL locus.Hum Mol Genet. 1993; 2: 279-282Crossref PubMed Scopus (43) Google Scholar mapping to the VHL region on chromosome 3p25-p26. Microsatellites were amplified from 50 to 150 ng of genomic DNA using 6 pmol of the corresponding primer pairs, with one primer carrying an IRD-41 label, in polymerase chain reaction (PCR) buffer (Perkin Elmer, Norwalk, CT) with 200 mmol/L each of dATP, dCTP, dGTP, and dTTP and 1.25 U of Taq DNA polymerase (Perkin Elmer) in a total reaction volume of 25 μl. PCR was performed on an Eppendorf Mastercycler 5330 using the following conditions: denaturation at 95°C for 5 minutes, 35 cycles with 95°C for 20 seconds, 62°C (D3S1350) or 56°C (D3S1038) for 20 seconds, and 72°C for 50 seconds, followed by a final extension step of 5 minutes at 72°C. PCR products were separated on 5% LongRanger gels (FMC BioProducts, Denmark), and the band densities were measured using a LICOR DNA sequencer 4000 (MWG Biotech) and RFLPscan software (Scanalytics, CSPI). The percent integrated optical density values of the bands representing the two alleles were compared with each other and with those obtained from normal tissue. LOH was scored if the decrease in optical density between one band and the corresponding allele in normal tissue was >60%. Statistical differences in the prevalence of the most common gains and losses between the primary and metastatic tumors were analyzed using Fisher's exact test. The degree of clonal relationship (CR) between primary tumors and metastases by CGH was based on a probabilistic model developed by a mathematician (A. A. Schäffer).20Kuukasjärvi T Karhu R Tanner M Kähkönen M Schäffer A Nupponen N Pennanen S Kallioniemi A Kallioniemi O Isola J Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer.Cancer Res. 1997; 57: 1597-1604PubMed Google Scholar Intuitively, the primary tumors and metastases should have a high probability to be clonally related if they share a set of gains and losses not likely to be shared at random. The following probabilistic model was developed to quantify this intuition. 1. Let a1, a2, a3, and so forth be the specific abnormalities. The probability that ai occurs is p(ai) = number of occurrences of ai/number of tumors. 2. P = set of aberrations in the primary tumor; M = set of aberrations in the metastasis. For any patient, the events in common are P ∩ M = c1, c2, c3,… ck. 3. p(ci) is the probability of the event (gain or loss) ci in the data set. The probability that the shared events occurred independently in the two tumors of the same patient is p(c1) × p(c2) × p(ck) = X. Thus, when the tumors have no events in common, the product defining X has no terms; it is standard in probability theory that such an empty product is defined as 1. The standard definition makes sense here because the events in common, the probability of a CR is estimated as 1 − X. Thus, when the tumors have no events in common, the probability of a CR is estimated as 0. Gains and losses were classified by chromosome arm, and the analysis ignored the band intervals. There was a high number of genetic changes in RCC metastases. The mean number (±SD) of changes per specimen was 8.1 ± 6.7 (median, 7; range, 1 to 29). The mean number of losses per tumor was 4.6 ± 4.5 (median, 3.5; range, 0 to 19), the mean number of gain per tumor 3.6 ± 3.4 (median, 3; range, 0 to 18). The most common gains were seen at 8q (22%), 17q (31%), 20q, 21q (22% each), and Xq (28%). There was one high-level gene amplification at chromosome 11q22–23. The most common losses involved 2q (22%), 3p (25%), 4q (28%), 6q (28%), 8p (31%), 9p (47%), and 10q, 13q, and 18q (22% each). Primary sites of metastatic dissemination in patients with RCC are lungs and lymph nodes.2Weiss L Harlos JP Torhorst J Gunthard B Hartveit F Svendsen E Huang WL Grundmann E Eder M Zwicknagl M Metastatic patterns of renal carcinoma: an analysis of 687 necropsies.J Cancer Res Clin Oncol. 1988; 114: 605-612Crossref PubMed Scopus (121) Google Scholar In an effort to evaluate whether the pattern of metastatic dissemination of cancer is associated with a specific chromosomal alteration, we analyzed lymph node metastases, lung metastases, and other metastatic sites as groups. The number of aberrations in lung metastases (6.2 ± 4.0) was significantly lower than in other hematogenous metastases (11.5 ± 8.7, P < 0.05). Also, the number of aberrations in lymph node metastases (4.8 ± 2.8) was lower than in hematogenous metastases (P < 0.05), excluding lung metastases. The number of aberrations was not different in lung and lymph node metastases (P = 0.6). The most frequent aberrations were also tested for an association with the metastatic site. No significant differences were found between specific aberrations and location of metastasis. The most common losses in 19 primary tumors involved 3p (63%), 4q (26%), 6q (21%), and 9p (26%). Gains were frequently detected at 7p (21%) and 16q (32%). None of the genetic changes in primary tumors had a frequency difference with the metastases significant at the P < 0.05 level when evaluated as a group. Closest to a significant difference were 3p losses. Chromosomal losses on 3p occurred in 12 of 19 primary tumors (63%) but in only 8 of 32 metastases (25%). The pairwise analysis revealed that primary tumors and their corresponding metastases were never identical. The degree of clonal relationship between the primary and metastatic cell clones varied substantially from one patient to another. For example, several tumors and their metastases shared three to four genetic changes and had only one different aberration. At the other end of the spectrum, there was a metastasis with 23 genetic changes, and only two of them could be discovered in the corresponding primary tumor. One example for a tumor pair without shared genetic changes is shown in Figure 1. In 14 patients, the metastases had more genetic aberrations than the corresponding primary tumor, whereas in 5 patients, fewer genetic alterations were found in the metastases. Genomic changes, which frequently occurred in metastases but not in the corresponding primary tumor, included 8p− (26%), 9p−, 17q+ (21. each), 21q+ (26%), and Xq+ (21%). The number of shared genetic changes is a rough estimate of the degree of clonal relationship between primary tumor and metastasis. Commonly occurring genetic changes are likely to be shared between two specimens, whereas more infrequent changes provide strong evidence for a common clonal progenitor. A mathematical model was developed to more accurately quantify the degree of clonal relationship by estimating the probability that shared genetic changes in the paired specimens are not likely to be shared by chance alone.20Kuukasjärvi T Karhu R Tanner M Kähkönen M Schäffer A Nupponen N Pennanen S Kallioniemi A Kallioniemi O Isola J Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer.Cancer Res. 1997; 57: 1597-1604PubMed Google Scholar According to this statistical analysis, 11 of the 19 paired specimens had a high probability (>0.8) for being clonally related. In seven of these cases, the probability was ≥0.9 (Figure 2). In six patients (32%), the genetic changes were completely different between the primary and metastatic lesions, so that no probability of a common clonal progenitor emerged. In two cases, the few shared genetic changes between the two specimens were likely to be attributable to chance alone. No significant relationships were found in the clinical and pathological parameters and the degree of clonal relationship. Metastases from different anatomical sites were available from three patients. The genetic composition of these metastases was never identical (Table 1). In one patient, the lymph node metastasis had seven, the lung metastasis three, and a metastasis in the diaphragm had nine aberrations. Lymph node and lung metastases shared one (18q+), whereas lymph node and diaphragm metastasis shared four aberrations (8p−, 9p−, 10q, and 15q−). Compared with the primary tumor, additional alterations were detected in all three metastatic locations. Another patient with metastasis to lung and peritoneum showed 10 DNA-sequence copy number changes in the lung and 17 in the peritoneum. Both metastases shared seven aberrations (1p−, 6q−, 7p−, 8p−, 8q+, 11p−, and12q+). The peritoneal tumor revealed additional aberrations (1q+, 3p−, 5p+, 7q+, 11q+, 14q−, 15q−, 17p+, 17q+, and 20p−) that were not present in the lung. Brain and lung metastases of a third patient had no identical alterations. The number of aberrations in these metastases was 6 and 11 per tumor.Table 1CGH of Metastases at Different LocationsPatient 1Patient 2Patient 3Primary tumor3p−, 4q−, 6q−, 9p−, 11q+, 18q−,Lymph node8p−, 9p−, 9q−, 10q−, 15q−, 17p+, 17q+Lung5q+, 17q+, 18q+1p−, 6q−, 7p−, 8p−, 8q+, 11p−, 12q+, 21q+, Xp−, Xq−,2q−, 3p−, 4p−, 4q−, 6q−, 9p−, 13q−, 17p+, Xp+, Xq+, Y−Diaphragm4p−, 5q+, 8p−, 9p−, 9q−, 10q−, 12q+, 13q+, 15q−Peritoneum1p−, 1q+, 3p−, 5p+, 6q−, 7p−, 7q+, 8p−, 8q+, 11p−, 11q+, 12q+, 14q−, 15q−, 17p+, 17q+, 20p−Brain8p−, 2p+, 5p+, 5q+, 15q+, 17q+ Open table in a new tab It has been suggested that chromosome 3p deletions are involved in initiation of clear-cell RCC.28Zbar B Brauch H Talmadge C Linehan M Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma.Nature. 1987; 327: 721-727Crossref PubMed Scopus (581) Google Scholar, 29van den Berg A Buys C Involvement of multiple loci on chromosome 3 in renal cell cancer development.Genes Chromosomes & Cancer. 1997; 19: 59-76Crossref PubMed Scopus (95) Google Scholar If VHL loss is an early event in RCC carcinogenesis, LOH of VHL should be present in both primary tumor and metastasis. To further investigate the unexpected result of more 3p losses in primary tumors than in corresponding metastases, loss of heterozygosity (LOH) of VHL was evaluated, because microsatellite analysis is more sensitive than CGH. We analyzed LOH for VHL in all patients with paired specimens (Table 2). One patient was excluded because no normal tissue was available. Thirteen patients were informative (heterozygous) for the VHL locus. The correspondence of 3p alterations in primary tumors and metastases was higher in the LOH analysis than in the CGH analysis. Seven primary tumors (54%) showed LOH for VHL. In metastases, LOH for VHL occurred in six cases (46%). There was only one tumor with a VHL deletion in the primary tumor but not in the corresponding metastasis (Figure 3). Two additional metastases (11%) had microsatellite instability at the VHL locus.Table 2LOH for VHL in 18 Matched Pairs of Primary RCC and Their MetastasesPatientPrimaryMetastasis1LOHLOH2n.i.n.i.3LOHLOH4−−5LOHLOH6n.i.n.i.7LOHLOH8LOHLOH9−−10−MIN11LOHLOH12−−13n.i.n.i.14−−15LOH−16n.i.n.i.17n.a.n.a.18−MIN19n.i.n.i.LOH, loss of heterozygosity; −, no loss of heterozygosity; n.i., not informative; MIN, microsatellite instability; n.a., no normal tissue available. Open table in a new tab LOH, loss of heterozygosity; −, no loss of heterozygosity; n.i., not informative; MIN, microsatellite instability; n.a., no normal tissue available. In this study, CGH was used to analyze the genetic basis underlying metastatic progression of RCC. It showed that metastases are genetically highly complex. The number of genetic aberrations detected in metastases (8.1 per tumor) was clearly higher than the number previously found in primary clear-cell (4.2 per tumor. RCC.10Moch H Presti Jr, JC Sauter G Buchholz N Jordan P Mihatsch MJ Waldman FM Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma.Cancer Res. 1996; 56: 27-30PubMed Google Scholar This is consistent with the theory that RCC progression from nonmetastatic primary tumors to metastasis is driven by an accumulation of genetic changes.30Presti J Rao H Chen Q Reuter V Li F Fair W Jhanwar S Histopathological, cytogenetic, and molecular characterization of renal cortical tumors.Cancer Res. 1991; 51: 1544-1552PubMed Google Scholar Several previous studies have suggested that a high number of CGH aberrations goes along with dedifferentiation and poor prognosis in RCC and other malignancies.10Moch H Presti Jr, JC Sauter G Buchholz N Jordan P Mihatsch MJ Waldman FM Genetic aberrations det" @default.
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• W2040155712 date "1999-07-01" @default.
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• W2040155712 title "Evaluation of the Clonal Relationship between Primary and Metastatic Renal Cell Carcinoma by Comparative Genomic Hybridization" @default.
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