Cytogenetic and molecular findings in 75 clear cell renal cell carcinomas

Cytogenetic analysis of 75 clear cell renal cell carcinomas (RCC) from adult patients revealed abnormal karyotypes in 59 (79%) tumors. Among structural abnormalities, the most frequent were deletions and unbalanced translocations leading to loss of 3p (found in 68% of karyotypically abnormal tumors), followed by rearrangements of chromosomes 5 (in 37%) and 1 (in 20%). Fifteen unbalanced interchromosomal rearrangements and one reciprocal translocation have not been hitherto reported in clear cell RCC. The most common numerical aberrations were trisomy 7, seen in 44% of tumors, and loss of chromosome Y, detected in 48% of RCCs diagnosed in male patients. In 25 tumors, loss of heterozygosity (LOH) analysis was performed using five polymorphic markers spanning region 3p13-p25. LOH was identified in 10 RCCs with 3p loss detected cytogenetically and 4 karyotypically aberrant tumors without cytogenetic rearrangements of 3p; no LOH was found in 3 tumors with 3p loss seen at the cytogenetic level. Overall, 3p loss was detected by cytogenetic and/or LOH analyses in 75% of RCCs with abnormal karyotype studied. The presence or absence of 3p loss did not correlate with tumor size, nodal involvement, tumor grade or its ability to metastasize. However, karyotypes of metastasizing tumors contained more aberrations than those of non-metastasizing RCCs (5.5 versus 2.9 aberrations per tumor, respectively), and -14/14q-, -17 and -10 were significantly more frequent in metastasizing tumors, suggesting that these aberrations might contribute to the progression of RCC. One patient had t(X;1)(p11.2;p34) as a sole abnormality in the stemline. This is the sixth case with this translocation reported to date. Together with our case, all but 1 RCC with t(X;1)(p11.2;p34) had morphology with a clear cell component, which contrasts these RCCs from tumors harboring t(X;1)(p11.2;q21) that largely had papillary morphology.     

The prognostic significance of cytogenetics and molecular profiling in multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy characterized by very complex cytogenetic and molecular genetic aberrations. In newly diagnosed symptomatic patients, the modal chromosome number is usually either hyperdiploid with multiple trisomies or hypodiploid with one of several types of immunoglobulin heavy chain (Ig) translocations. The chromosome ploidy status and Ig rearrangements are two genetic criteria that are used to help stratify patients into prognostic groups based on the findings of conventional cytogenetics and fluorescence in situ hybridization (FISH). In general, the hypodiploid group with t(4;14)(p16;q32) or t(14;16)(q32;q23) is considered a high-risk group, while the hyperdiploid patients with t(11;14)(q13;q32) are considered a better prognostic group. As the disease progresses, it becomes more proliferative and develops a number of secondary chromosome aberrations. These secondary aberrations commonly involve MYC rearrangements, del(13q), del(17p), and the deletion of 1p and/or amplification of 1q. Of the secondary aberrations, del(17p) is consistently associated with poor prognosis. All of these cytogenetic aberrations and many additional ones are now identified by means of high resolution molecular profiling. Gene expression profiling (GEP), array comparative genomic hybridization (aCGH), and single-nucleotide polymorphism (SNP) arrays have been able to identify novel genetic aberration patterns that have previously gone unrecognized. With the integration of data from these profiling techniques, new subclassifications of MM have been proposed which define distinct molecular genetic subgroups. In this review, the findings from conventional cytogenetics, interphase FISH, GEP, aCGH, and SNP profiles are described to provide the conceptual framework for defining the emerging molecular genetic subgroups with prognostic significance.     

The genetic locus NRC-1 within chromosome 3p12 mediates tumor suppression in renal cell carcinoma independently of histological type, tumor microenvironment, and VHL mutation

Human chromosome 3p cytogenetic abnormalities and loss of heterozygosity have been observed at high frequency in the nonpapillary form of sporadic renal cell carcinoma (RCC). The von Hippel-Lindau (VHL) gene has been identified as a tumor suppressor gene for RCC at 3p25, and functional studies as well as molecular genetic and cytogenetic analyses have suggested as many as two or three additional regions of 3p that could harbor tumor suppressor genes for sporadic RCC. We have previously functionally defined a novel genetic locus nonpapillary renal carcinoma-1 (NRC-1) within chromosome 3p12, distinct from the VHL gene, that mediates tumor suppression and rapid cell death of RCC cells in vivo. We now report the suppression of tumorigenicity of RCC cells in vivo after the transfer of a defined centric 3p fragment into different histological types of RCC. Results document the functional involvement of NRC-1 in not only different cell types of RCC (i.e., clear cell, mixed granular cell/clear cell, and sarcomatoid types) but also in papillary RCC, a less frequent histological type of RCC for which chromosome 3p LOH and genetic aberrations have only rarely been observed. We also report that the tumor suppression observed in functional genetic screens was independent of the microenvironment of the tumor, further supporting a role for NRC-1 as a more general mediator of in vivo growth control. Furthermore, this report demonstrates the first functional evidence for a VHL-independent pathway to tumorigenesis in the kidney via the genetic locus NRC-1.     

Histopathological, cytogenetic, and molecular characterization of renal cortical tumors.

We used cytogenetic and restriction fragment length polymorphism (RFLP) analysis methods to define genetic alterations and also correlate the changes with histopathology in renal cortical tumors. The study series is comprised of 50 renal tumors in 4 histological categories: (a) clear cell, nonpapillary, renal cell carcinoma (RCC) (n = 32); (b) nonclear cell, nonpapillary RCC (n = 10); (c) papillary RCC (n = 3); and (d) oncocytic tumors (n = 5). Successful karyotypes were obtained from 28 tumors (56%), of which 17 (61%) were abnormal. Abnormalities of chromosome 3p were seen in 9 tumors, which included unbalanced translocations and terminal or interstitial deletions. Abnormalities of chromosome 5 were identified in 11 tumors, 8 of which were due to unbalanced translocations between 3p and 5q, resulting in an extra copy for the region 5q22----ter. In addition, trisomy or tetrasomy of chromosome 17 was seen in 6 (5 with normal chromosome 3 and one with 3p deletion), trisomy or more copies of chromosome 7 in 8 (4 with 3p deletion, 2 with trisomy or tetrasomy 17, and 2 with trisomy alone), and trisomy 12 in 3 (all with trisomy 17) tumors. Furthermore, relative deficiency of chromosome 17p was seen in 3 (all with deletion 3p) and chromosome 18 in 4 (all with deletion 3p) tumors. RFLP analysis with four chromosome 3 specific probes detected 3p deletions in 19 tumors with the most common breakpoint located between 3p14-21. The 19 3p deletions detected by RFLP included tumors that also showed rearrangement of 3p by cytogenetics (n = 4) and those that showed normal karyotypes (n = 3) in addition to cytogenetic failures (n = 12). Deletions of 17p were seen in 5 of 31 informative cases. Thus, deletions of 3p were seen in a total of 24 tumors by cytogenetic and/or RFLP analysis, 21 of which were clear cell, nonpapillary RCC, whereas 3 had a minor clear-cell component. Oncocytic and nonclear, nonpapillary tumors, on the other hand, did not demonstrate 3p deletions by either technique, whereas trisomy 17 was seen in 3 of the 3 papillary tumors. The loss of alleles from chromosome 17p and 18 and an increased dosage of gene or genes on chromosomes 5q and 7 as seen in high-stage tumors of various histological subtypes may be associated with progression of disease.     

Cytogenetic findings in 14 benign cartilaginous neoplasms

Benign cartilaginous tumors represent a spectrum of neoplastic processes with variable clinical and pathologic presentations. These tumors are histologically characterized by the presence of chondrocytes surrounded by a cartilaginous matrix. Few studies describe karyotypic abnormalities in these benign lesions. We report a series of 14 chondromas from a single institution. Conventional cytogenetics was performed on short term cultures from all cases. Clonal chromosome aberrations were found in nine tumors. One soft tissue chondroma contained three clones with t(6;12)(q12;p11.2), t(3;7)(q13;p12), and der(2)t(2;18)(p11.2;q11.2). Three periosteal chondromas displayed random structural aberrations of chromosomes 2, 3, 6, 7, and 11 and loss of chromosome 13. Among the enchondromas, three tumors displayed chromosome losses, one contained a complex translocation involving chromosomes 12, 15, and 21 as well as an inv(2)(p21q31),t(12;15;21)(q13;q14;q22) and a separate enchondroma showed a translocation involving chromosomes 12 and 22. Our data suggest that considerable cytogenetic heterogeneity exists among benign chondromatous tumors.     

Genetic clustering of clear cell renal cell carcinoma based on array-comparative genomic hybridization: its association with DNA methylation alteration and patient outcome

PURPOSE: The aim of this study was to clarify genetic and epigenetic alterations occurring during renal carcinogenesis. EXPERIMENTAL DESIGN: Copy number alterations were examined by array-based comparative genomic hybridization analysis using an array harboring 4,361 bacterial artificial chromosome clones, and DNA methylation alterations on CpG islands of the p16, human MutL homologue 1, von Hippel-Lindau, and thrombospondin 1 genes and the methylated in tumor (MINT-1, MINT-2, MINT-12, MINT-25, and MINT-31) clones were examined in 51 clear cell renal cell carcinomas (RCC). RESULTS: By unsupervised hierarchical clustering analysis based on copy number alterations, clear cell RCCs were clustered into the two subclasses, clusters A (n=34) and B (n=17). Copy number alterations were accumulated in cluster B. Loss of chromosome 3p and gain of 5q and 7 were frequent in both clusters A and B, whereas loss of 1p, 4, 9, 13q, and 14q was frequent only in cluster B. The average number of methylated CpG islands in cluster B was significantly higher than those in cluster A. Clear cell RCCs showing higher histologic grades, vascular involvement, renal vein tumor thrombi, and higher pathologic stages were accumulated in cluster B. The recurrence-free and overall survival rates of patients in cluster B were significantly lower than those of patients in cluster A. Multivariate analysis revealed that genetic clustering was a predictor of recurrence-free survival and was independent of histologic grade and pathologic stage. CONCLUSIONS: This genetic clustering of clear cell RCC is significantly associated with regional DNA hypermethylation and may become a prognostic indicator for patients with RCC.     

Cytogenetic findings in pediatric germ-cell tumors

Three pediatric germ cell tumors (GCT) were cytogenetically analyzed. A mediastinal mature teratoma in a 15-year-old girl had a balanced t(8;22)(p21;q12) as the sole clonal aberration, an intrathoracic immature teratoma in a 2-year-old girl had the complex karyotype 46,XX,der(6) ins(6;2)(q15;q11q23),de1(8)(q22),-1O,der(12)t(10;12),(q22;q22- 23),der(16)t(1;16)(q12;q11),+mar and a congenital presacral endodermal sinus tumor was characterized by the karyotype 47,XY,add(11)(p15),der(13)t(1;13)(q21;p13),add(14)(p13),d e1(15)(q24),+der(?)t(?;11)(?;q13). The present three tumors had no chromosome aberration in common, nor has any specific change been detected in the 13 previously reported cytogenetically aberrant pediatric GCT. The karyotypic picture comes across as far more heterogeneous than that of GCT of adults. Whereas gain of 12p material, in the vast majority through i(12)(p10) formation, dominates in the adult setting, the most common cytogenetic abnormalities in pediatric GCT seem to be unbalanced recombinations leading to gain of 1q. Other recurrent changes include, in decreasing order of frequency, numerical and structural aberrations leading to gain of 8q and 12p, loss of distal 1p, +3, loss of 7q22-32, -10, -13 and -18.     

Molecular cytogenetic characterization of head and neck squamous cell carcinoma and refinement of 3q amplification

We applied a combination of molecular cytogenetic methods, including comparative genomic hybridization (CGH), spectral karyotyping (SKY), and fluorescence in situ hybridization, to characterize the genetic aberrations in a panel of 11 cell lines derived from head and neck squamous cell carcinoma and 1 cell line derived from premalignant oral epithelium. CGH identified recurrent chromosomal losses at 1p, 3p, 4, 8p, 10p, and 18q; gains at 3q, 5p, 8q, 9q, and 14q; and high-level amplification at 3q13, 3q25-q26, 5q22-q23, 7q21, 8q24, 11q13-q14, 12p13, 14q24, and 20q13.1. Several recurrent translocations including t(1;13)(q10;q10), t(13;13)(q10;q10), t(14;14)(q10;q10), i(8)(q10), and i(9)(q10) and breakpoint clusters at 1p11, 1q21, 3p11, 5q11, 5q13, 6q23, 8p11, 8q11, 9p13, 9q13, 10q11, 11q13, 13q10, 14q10, and 15q10 were identified by SKY. There was a good correlation between the number of aberrations identified by CGH and SKY (r = 0.69), and the analyses were both confirmatory and complementary in their assessment of genetic aberrations. Amplification at 3q26-q27 was identified in 42% of cases. Although SKY defined the derivation of 3q gain, the precise breakpoint remained unassigned. Positional cloning efforts directed at the amplified region at 3q26-q27 identified three highly overlapping nonchimeric yeast artificial chromosome clones containing the apex of amplification. The use of these yeast artificial chromosome clones as a probe for fluorescence in situ hybridization analysis allowed a detailed characterization and quantification of the 3q amplification and refinement of unassigned SKY breakpoints.     

Comparative genomic hybridization of esophageal squamous cell carcinoma: correlations between chromosomal aberrations and disease progression/prognosis.

BACKGROUND: Esophageal carcinoma is a major cause of cancer-related deaths among males in Taiwan. However, to date, the genetic alterations that accompany this lethal disease are not understood. METHODS: Chromosomal aberrations of 46 samples of esophageal squamous cell carcinoma (EC-SCC) were analyzed by comparative genomic hybridization (CGH), and their correlations with pathologic staging and prognosis were analyzed statistically. RESULTS: In total, 321 gains and 252 losses were found in 46 tumor samples; thus, the average gains and losses per patient were 6.98 and 5.47, respectively. Frequent gain abnormalities were found on chromosome arms 1q, 2q, 3q, 5p, 7p, 7q, 8q, 11q, 12p, 12q, 14q, 17q, 20q, and Xq. Frequent deletions were found on chromosome arms 1p, 3p, 4p, 5q, 8p, 9p, 9q, 11q, 13q, 16p, 17p, 18q, 19p, and 19q. It was found that deletions of 4p and 13q12-q14 and gain of 5p were significantly correlated with pathologic staging. Losses of 8p22-pter and 9p also were found more frequently in patients with advanced disease. Gain of 8q24-qter was seen more frequently in patients with Grade 3 tumors. A univariate analysis found that pathologic staging; gains of 5p and 7q; and deletions of 4p, 9p, and 11q were significant prognostic factors. However, pathologic staging became the only significant factor in a multivariate analysis. CONCLUSIONS: CGH not only revealed novel chromosomal aberrations in EC-SCC, but also found possible genotypic changes associated with disease progression. Despite all of the possible associations of chromosomal aberrations with disease progression, the most important prognostic factor for patients with EC-SCC was pathologic staging.     

Cytogenetic profile of 109 lipomas

Cytogenetic analysis of short-term cultures was carried out on 109 lipomas from 92 patients. Clonal chromosomal abnormalities were present in 50% of the tumors analyzed. Based on the results, three main cytogenetic groups were identified and included: (a) tumors with normal karyotypes, (b) tumors with abnormalities involving region q13-15 on chromosome 12, and (c) tumors with other clonal aberrations. Within each of these groups, cytogenetic subgroups could be identified, each characterized by a specific anomaly. Tumors with abnormalities of 12q included specific subgroups with t/ins(1;12)(p32-33;q13-15), t(2;12)(p21-22;q13-14), t(3;12)(q28;q14), t(12;21)(q13;q21), complex, and nonrecurrent aberrations. The group containing heterogeneous clonal aberrations included subgroups with del(13)(q12q22), der(6)(p21-23), der(11)(q13), and nonspecific aberrations. Chromosome bands 1p36, 1p32-33, 2p21-22, 3q27-28, 6p21-23, 11q13, 12q13-15, 13q12, 13q22, 17p13, 17q21, and 21q21-22 were preferentially involved in structural rearrangements in lipomas. The identification of these sites of nonrandom rearrangements may serve to identify genes (at or near the junctions of chromosomal aberrations) involved in normal cellular growth control. Statistical analysis of the data revealed a correlation among karyotypic abnormalities and clinical data, such as age and sex of the patient, and tumor depth, site, and size.     

Diagnostic and Prognostic Significance of Cytogenetics in Adult Primary Myelodysplastic Syndromes

Cytogenetic analysis has proven to be a mandatory part of the diagnosis of myelodysplastic syndromes (MDS) as well as a major indicator for predicting clinical course and outcome. This review concentrates on the cytogenetic classifications, the incidence and types of chromosome defects and the prognostic significance of the karyotype in adult primary MDS. Two cytogenetic classifications are currently used: one is based on the karyotype complexity (normal, single, double or complex defects), the other on clonal status (all metaphases normal, abnormal or admixture of normal and abnormal clones). Chromosome abnormalities are of both numerical and structural types. Aside from the 5q-syndrome, no specific clinico-cytogenetic entity has been reported. However, several distinct clinical and cellular features have been identified that correlate with the presence of specific chromosome defects such as inv(3)/t(3;3), +6, t(5;12), del(17p) and del(20q). The presence of complex defects is associated with reduced survival and a high risk of leukemic transformation. Among single defects, specific abnormalities may define distinct prognostic groups. Patients with del(5q) as a sole chromosome defect and a refractory anemia without excess of blasts have a favourable prognosis. For patients with trisomy 8 or monosomy 7 there may be distinct types of clinical evolution. Most patients with the 3q21q26 syndrome have a short survival. The presence of two chromosome defects may constitute an independent cytogenetic entity probably associated with relative poor prognosis. Karyotypic evolution generally represents a poor risk factor. The combination of cytogenetics with clinical and hematological features has proven to provide for a better prediction of patients' survival, leukemic transformation and response to treatment. Several scoring systems have been developed. They have to be improved by the study of new patients according to strict clinical and cytogenetic criteria and by the addition of newly recognized prognostic indicators such as histopathological features and molecular genetic mutations.     

Analysis of complex chromosomal rearrangements in adult patients with MDS and AML by multicolor FISH

We analyzed complex chromosomal aberrations in 37 adult patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) using classical cytogenetic method, FISH with locus-specific probes, multicolor FISH (mFISH) and multicolor banding (mBAND). Unbalanced structural aberrations, leading to a gain or loss of chromosomal material, were frequently observed in bone marrow cells. In 30 patients (81.1%) loss or rearrangement of chromosome 5, 7 and/or 11 was found. The most frequent numerical change was trisomy 8 as expected (detected in six patients-16.2%) and the most frequent breakpoints 5q13, 5q33, 7q31, 10p12, 11q23, 12p13, 17p11 and 21q22 were determined.     

Additional chromosome 1q aberrations and der(16)t(1;16), correlation to the phenotypic expression and clinical behavior of the Ewing family of tumors

The cytogenetic hallmark of the Ewing family of tumors is t(11;22)(q24;q12) in its simple, complex or variant forms and/or its molecular equivalent EWS/FLI, EWS/ERG rearrangement. Additional secondary consistent chromosomal aberrations include the der(16)t(1;16) and, frequently, other chromosome 1q abnormalities leading to 1q overdosage. We studied whether these secondary cytogenetic changes are correlated to clinical features and phenotypic expression which may have a prognostic impact.Successful cytogenetic evaluation was performed in eight patients with a Ewing family tumor. In four of these, in addition to the primary aberration, chromosome 1q overdosage (including two with der(16)t(1;16)) was noted. Out of these four patients, two had metastatic disease at the time of evaluation, while in the other four, disease was localized. Morphologically, the tumors with the additional 1q aberration, revealed the pPNET subtype more frequently than the typical Ewing. They also expressed a higher degree of neural differentiation by neural marker immunocytochemistry, in comparison to tumors without the 1q aberration.Determination of the prognostic significance of this finding requires a longer follow-up with a larger group of patients.     

Chromosome rearrangement at 17q25 and xp11.2 in alveolar soft-part sarcoma: A case report and review of the literature.

BACKGROUND: Despite the characteristic histopathologic appearance of alveolar soft-part sarcoma (ASPS), its histogenesis remains unclear, and cytogenetic analysis of ASPS is limited to eight cases so far because of the extreme rarity of this disease. METHODS: The authors document a cytogenetic study of a primary case of ASPS in which a modern spectral karyotyping technique was used. RESULTS: A standard cytogenetic analysis of the primary tumor cells with G-banding revealed 46,XY, add(17)(q25) in 23 of 25 metaphases analyzed. This structural rearrangement of chromosome 17, involving band q25, was also present in 5 of 8 ASPS cases in the literature. Moreover, with the spectral karyotyping technique, the additional part of the long arm of chromosome 17 in the current case was found to originate from chromosome X, resulting in a final tumor karyotype of 46, XY, add(17)(q25).ish der(17)t(X;17) (p11.2;q25)(wcpX+). CONCLUSIONS: This case report documents a clonal chromosome abnormality of der(17)t(X;17)(p11.2;q25) in ASPS. The results of the current study indicate that further molecular analyses focused on 17q25 and Xp11.2 are of interest and could help to elucidate the pathogenesis of ASPS.     

Genetic characterization of lung metastases in renal cell carcinoma

Prognosis of patients with renal cell carcinoma (RCC) is mainly determined by metastases. The understanding of the metastatic process will give the basis for a differential diagnosis leading to an individual prognosis and to new therapeutical strategies. In order to define specific genetic alterations which are common in renal cancer metastases of the lung, we performed comparative genomic hybridization (CGH) on metastases and in some cases on their related primary renal tumors. For CGH, DNA was isolated from 2 or 5 paraffin sections (5 micro m). Tumor and normal (control) DNAs were amplified by DOP-PCR and labeled with biotin-dUTP and digoxigenin-dUTP, respectively. Hybridization and detection were carried out according to standard protocols. In 33 out of 40 metastases, genetic alterations were detected, most frequently these were losses of chromosomes 3p (74%), 8p (31%), 9 or 9q (34%), 14 [26%, 18q (40%) and gains of chromosome 5/5q 34%], 7 (31%) and 12 (26%). Combination of loss of 8p and gain of 8q occurred frequently. The mean number of aberrations per tumor was 8.1 (1-11). The comparison of alterations in related primary and metastatic tumors showed identical alterations in 5 out of 8 cases. This study demonstrates, that lung metastases from renal cell carcinoma are characterized by an accumulation of specific genetic alterations which show a clonal relationship to the related primary tumors.     

Recurrent chromosome changes at 3p21 in Epstein-Barr virus-transformed cells derived from human prolymphocytic leukemia

Cytogenetic studies of Epstein-Barr virus-transformed lymphoblastoid cells obtained from a patient with prolymphocytic leukemia revealed the cells to contain recurrent chromosome aberrations involving band 3p21. The in vivo leukemic cells from which the cell lines originated contained a der(3)t(3;17?)(p21;q11?) and a der(13)t(13;3)(q34;p21), as well as numerical (-Y, -8, and -17) and other structural [8p- and der(8)t(8;?)(q13?;?)] changes. The cells in established culture showed additional chromosome aberrations involving band 3p21 of the previously normal and abnormal chromosomes 3. After 200 days of culture, the cells contained a new translocation, i.e., t(3;14)(p21;q32). The cells showed further chromosomal breakage and reunion at band 3p21 at later passages. The affected chromosomal band (3p21) is close to one of the constitutive fragile sites, i.e., 3p14.2. Northern blot analysis of the messenger RNA of the cultured cells did not show an increased or altered expression of the c-raf-1 protooncogene (located at 3p25) when compared with the mRNA of Epstein-Barr virus-transformed lymphoblastoid cell lines from normal subjects with a normal karyotype. Also, the established cells did not show DNA rearrangements or RNA alterations of the c-myc gene.     

Karyotypic aberrations in an anal-canal malignant-melanoma and its local metastasis

Tissue samples from a malignant melanoma of the anal canal and its local metastasis were short-term cultured and analyzed cytogenetically. Complex chromosome aberrations were found in the primary tumor, yielding the karyotype 49-50,X,-Y,der(1)t(1;13)(q44;q12),+der(2)t(2;8) (q31;q12),der(6)t(5;6)(q13;q21),+del(6)(q12q21),+7, der(8)t(6;8)(p12;p21),del(11)(p11),der(11)t(11;12) (p15;q24),der(15)t(6;15)(p21;p11-13),+der(20)t(1;20) (q12;q13),der(22)t(11;22)(p11;p11)[34]/88-100,idemx2[3]. In the local metastasis, the same near-tetraploid abnormal clone was detected, indicating that the cell population was clonally stable during tumor progression. This is the first malignant melanoma of the anal canal that has been cytogenetically characterized.     

Chromosome 3p Deletion in a Renal Cell Carcinoma Cell Line Established from a Patient with von Hippel-Lindau Disease

von Hippel-Lindau disease (VHL) is an autosomal dominant inheriteddisease, frequently accompanied by occurrences of renal cellcarcinoma (RCC). Both the VHL gene and tumor suppressor genesfor RCC have been mapped to the short arm of chromosome 3, althoughthe genes have not yet been identified. An RCC cell line, KC12,was established from a VHL patient. Molecular genetic analysesin conjunction with cytogenetic studies revealed that the shortarm of chromosome 3 distal to the D3S4 locus at 3p11 was lostin the RCC cell line as a result of an unbalanced translocationbetween chromosomes 3p and 5q. Structural and numerical aberrations,including those on chromosome 3p, were not detected in T-lymphocytesfrom the patient, suggesting that the inherited mutation ofthe VHL gene at 3p25-26 in this patient was too subtle to bedetected by either Southern blot or karyotype analysis. Sinceno permanent RCC cell line has been established from a VHL patient,this cell line will be a useful source for analyzing the VHLgene at 3p25-26 and tumor suppressor gene(s) at 3p13-21.