Immunohistopathological characterization and the impact of topical immunomodulatory therapy in oral chronic graft-versus-host disease: A pilot study.

OBJECTIVE: To characterize the immunohistopathological features of oral chronic graft-versus-host disease (cGVHD), and the impact of topical immunomodulatory therapy on the infiltrating cells. MATERIAL AND METHODS: Paired oral cGVHD biopsies obtained before (n = 12) and 1 month after treatment (n = 12) with topical dexamethasone (n = 8) or tacrolimus (n = 4) were characterized by immunohistochemistry using a panel of CD1a, CD3, CD4, CD8, CD20, CD31, CD62E, CD103, CD163, c-kit, and FoxP3. Controls included acute GVHD (aGVHD; n = 3), oral lichen planus (OLP; n = 5), and normal tissues (n = 5). RESULTS: Oral cGVHD specimens prior to treatment were mainly characterized by basal cell squamatization, lichenoid inflammation, sclerosis, apoptosis, and lymphocytic exocytosis. The infiltrating cells in oral cGVHD primarily consisted of CD3+ , CD4+ , CD8+ , CD103+ , CD163+ , and FoxP3+ cells, which were higher than in normal tissues. Topical dexamethasone or tacrolimus reduced neutrophilic exocytosis, basal cell squamatization, and lichenoid inflammation in oral cGVHD, and dexamethasone reduced the number of CD4+ and CD103+ cells. CONCLUSION: The high expression of CD3, CD4, CD8, CD103, CD163, and FoxP3 confirms that oral cGVHD is largely T-cell-driven with macrophage participation. The impact of topical immunomodulatory therapy was variable, reducing histological inflammatory features, but with a weak clinicopathological correlation. Topical dexamethasone reduced the expression of CD4 and CD103, which may offer novel therapeutic targets.

Evaluation of the reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index and the Cutaneous Assessment Tool-Binary Method in juvenile dermatomyositis among paediatric dermatologists, rheumatologists and neurologists.

BACKGROUND: The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) and Cutaneous Assessment Tool-Binary Method (CAT-BM) have been shown to be reliable and valid outcome measures to assess cutaneous disease in adult dermatomyositis (DM) and juvenile DM (JDM), respectively. OBJECTIVES: This study compared the CDASI and CAT-BM for use by paediatric dermatologists, paediatric rheumatologists and paediatric neurologists in patients with JDM. METHODS: Five paediatric dermatologists, five paediatric rheumatologists and five paediatric neurologists each evaluated 14 patients with JDM using the CDASI, CAT-BM, and skin Physician Global Assessment (PGA) scales. Inter-rater reliability, intra-rater reliability, construct validity and completion time were compared. RESULTS: Inter-rater reliability for CDASI activity and damage scores was good to moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists. The inter-rater reliability for CAT-BM activity scores was moderate for paediatric dermatologists and rheumatologists, but poor for paediatric neurologists and poor across all specialties for damage scores. Intra-rater reliability for the CDASI and CAT-BM activity and damage scores was moderate to excellent for paediatric dermatologists, rheumatologists and neurologists. Strong associations were found between skin PGA activity and damage scores and CDASI or CAT-BM activity and damage scores, respectively (P < 0·002). The CDASI had a mean completion time of 5·4 min compared with that for the CAT-BM of 3·1 min. CONCLUSIONS: Our data confirm the reliability of the CDASI activity and damage scores and the CAT-BM activity scores when used by paediatric dermatologists and rheumatologists in assessing JDM. Significant variation existed in the paediatric neurologists' scores.

Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.

Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.

Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease.

Four clones were isolated from an adult human brain complementary DNA library with an oligonucleotide probe corresponding to the first 20 amino acids of the beta peptide of brain amyloid from Alzheimer's disease. The open reading frame of the sequenced clone coded for 97 amino acids, including the known amino acid sequence of this polypeptide. The 3.5-kilobase messenger RNA was detected in mammalian brains and human thymus. The gene is highly conserved in evolution and has been mapped to human chromosome 21.

Dental panoramic radiographic evaluation in bisphosphonate-associated osteonecrosis of the jaws.

OBJECTIVES: To determine the extent to which clinical and radiographic features of bisphosphonate-associated osteonecrosis of the jaw (BONJ) are correlated. DESIGN: Retrospective case review. METHODS: The records of 39 patients diagnosed with BONJ and examined by panoramic radiography were retrospectively evaluated. The arches were divided into sextants (n = 234) and evaluated for the following signs: sclerosis, surface irregularity, sockets, fragmentation and lysis. MAIN OUTCOME MEASURES: The McNemar, Kruskall-Wallis and equivalency tests were performed to analyze the association between clinical and radiographic signs and BONJ severity. RESULTS: Sixty-two out of 234 sextants were abnormal by clinical criteria and 61 out of 234 sextants demonstrated at least one radiographic abnormality. There was agreement between clinical and radiographic detection in 41 sextants. The data showed equivalency between BONJ diagnosis and both sclerosis and surface irregularity. The correlation between number of clinical sites and any radiographic finding was significant in the maxilla (P < 0.001) but not in the mandible (P = 0.178). The total number of radiographic signs per patient increased with BONJ stage. CONCLUSION: Focal panoramic radiographic findings of sclerosis and surface irregularity correlate with clinical sites of BONJ. This may be a useful and reliable tool to detect early changes of BONJ or to confirm a clinical diagnosis.

Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13.

DEC1/STRA13 is a bHLH type transcriptional regulator involved with immune regulation, hypoxia response and carcinogenesis. We recently demonstrated that STRA13 interacts with STAT3 in the transcriptional activation of STAT-dependent promoters. Here, we pursue STRA13 involvement in the JAK/STAT pathway by studying its role in STAT1 expression. First, we showed that VHL deficiency or HIF-1 activation resulted in the repression of endogenous STAT1 mediated by STRA13. We then characterized the STAT1 proximal promoter to assess its response to STRA13 by transient coexpression in a luciferase reporter assay. Using sequential truncation and site-directed mutagenesis of the STAT1 promoter with STRA13 deletion constructs, we showed that the STRA13 C-terminal trans-activation domain, which is known to bind HDAC1, mostly determines the repressive activity. Involvement of HDAC activity in STAT1 regulation was validated by TSA inhibition and chromatin immunoprecipitation (ChIP) assay. Thus, we demonstrate that STRA13-mediated repression of STAT1 transcription utilizes an HDAC1-dependent mechanism. Furthermore, we show that targets of unphosphorylated STAT1, such as antigen presenting genes and CASP1, are also repressed by hypoxia possibly through the same STRA13-mediated mechanism. Thus, the newly discovered link between HIF-1 and STAT1 reveals a previously unknown role of STRA13 in hypoxia and carcinogenesis.

Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter.

The gene for tyrosine-kinase receptor Ron (MST1R) resides in the chromosome 3p21.3 region, frequently affected in common human malignancies. The gene generates two transcripts, 5 and 2 kb-long, full-length Ron (flRon) and short-form Ron (sfRon), respectively. Here, we show for the first time that the variegated Ron expression is associated with variations in the methylation patterns of two distinct CpG islands in Ron proximal promoter. Widespread hypermethylation associates with lack of flRon whereas hypermethylation of the distal island associates with transcription of sfRon, a constitutively active tyrosine-kinase that drives cell proliferation. sfRon inhibition with kinase-dead transgenes decreases cancer cell growth and induces cellular differentiation. sfRon could be a new drug target in cancer types in which it contributes to tumor progression.

Single center observation of the role of pre-existing HLA-DP antibodies in humoral rejection following renal transplantation.

HLA antigens, including HLA-A, B, C, DR and DQ have long been known to have an effect on transplant outcome. Presence of antibodies to these antigens is detrimental to transplant outcome as it ends up to either acute or chronic humoral rejection depending on the titer of the antibodies to these antigens. However, the role of HLA-DP is not fully clear, predominantly due to lack of adequate publications and the fact that DP antigen and antibody detection became possible with the advent of new beads technology. As a results, allocation system has not yet included HA-DP antibodies in virtual crossmatching. This report presents two novel cases with strong HLA-DP antibodies which resulted in acute humoral rejection (AMR).

Unusual class of Alu sequences containing a potential Z-DNA segment.

A potential Z-DNA sequence, (dA-dC)9, has been found to replace the customary A-rich region in the middle of an Alu family member in the African green monkey genome. This Alu, bounded by imperfect direct repeats, also contains an unusual 3' end and may be a member of a large subfamily of such sequences.

A transforming activity not detected by DNA transfer to NIH 3T3 cells is detected by JB6 mouse epidermal cells.

Transfection of four different mouse epidermal tumor cell DNAs into NIH 3T3 cells yielded neither morphologically altered foci nor anchorage independence. However, promotion-sensitive, but not promotion-insensitive, JB6 mouse epidermal cell lines were permissive for the expression of anchorage independence after transfection of DNA from three of these tumor cell lines. This transforming activity and the promotion-sensitive activity that confers sensitivity to promotion of transformation show differences in restriction enzyme sensitivity. In view of this difference and the differences in both recipient cells and 12-O-tetradecanoyl-phorbol-13-acetate dependence of expression, it appears that the transforming activity and the promotion-sensitive activity are specified by different genes. The JB6 promotion-sensitive cell lines may be useful for detecting and cloning transforming genes that escape detection in the NIH 3T3 cell focus assay.

Protective function of von Hippel-Lindau protein against impaired protein processing in renal carcinoma cells.

The absence of functional von Hippel-Lindau (VHL) tumor suppressor gene leads to the development of neoplasias characteristic of VHL disease, including renal cell carcinoma (RCC). Here, we compared the sensitivity of RCC cells lacking VHL gene function with that of RCC cells expressing the wild-type VHL gene (wtVHL) after exposure to various stresses. While the response to most treatments was not affected by the VHL gene status, glucose deprivation was found to be much more cytotoxic for RCC cells lacking VHL gene function than for wtVHL-expressing cells. The heightened sensitivity of VHL-deficient cells was not attributed to dissimilar energy requirements or to differences in glucose uptake, but more likely reflects a lesser ability of VHL-deficient cells to handle abnormally processed proteins arising from impaired glycosylation. In support of this hypothesis, other treatments which act through different mechanisms to interfere with protein processing (i.e., tunicamycin, brefeldin A, and azetidine) were also found to be much more toxic for VHL-deficient cells. Furthermore, ubiquitination of cellular proteins was elevated in VHL-deficient cells, particularly after glucose deprivation, supporting a role for the VHL gene in ubiquitin-mediated proteolysis. Accordingly, the rate of elimination of abnormal proteins was lower in cells lacking a functional VHL gene than in wtVHL-expressing cells. Thus, pVHL appears to participate in the elimination of misprocessed proteins, such as those arising in the cell due to the unavailability of glucose or to other stresses.

p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein.

Regulated cyclin-dependent kinase (CDK) levels and activities are critical for the proper progression of the cell division cycle. p12(DOC-1) is a growth suppressor isolated from normal keratinocytes. We report that p12(DOC-1) associates with CDK2. More specifically, p12(DOC-1) associates with the monomeric nonphosphorylated form of CDK2 (p33CDK2). Ectopic expression of p12(DOC-1) resulted in decreased cellular CDK2 and reduced CDK2-associated kinase activities and was accompanied by a shift in the cell cycle positions of p12(DOC-1) transfectants ( upward arrow G(1) and downward arrow S). The p12(DOC-1)-mediated decrease of CDK2 was prevented if the p12(DOC-1) transfectants were grown in the presence of the proteosome inhibitor clasto-lactacystin beta-lactone, suggesting that p12(DOC-1) may target CDK2 for proteolysis. A CDK2 binding mutant was created and was found to revert p12(DOC-1)-mediated, CDK2-associated cell cycle phenotypes. These data support p12(DOC-1) as a specific CDK2-associated protein that negatively regulates CDK2 activities by sequestering the monomeric pool of CDK2 and/or targets CDK2 for proteolysis, reducing the active pool of CDK2.

Selection of CD4+CD25+ regulatory T cells by self-peptides.

Regulatory T cells have been shown to prevent the development of autoimmune disease, and can modulate immune responses during infections or following tissue transplantation. Recently, the processes by which CD4+CD25+ regulatory T cells are produced during immune repertoire formation have begun to be elucidated. This review focuses on the role of self-peptides in mediating CD4+CD25+ regulatory T cell selection in the thymus. How self-peptides continue to have an important influence on the accumulation of CD4+CD25+ regulatory T cells in the periphery is also discussed.

STRA13 expression and subcellular localisation in normal and tumour tissues: implications for use as a diagnostic and differentiation marker.

BACKGROUND: STRA13 is a bHLH transcription factor that plays a crucial role in cell differentiation, proliferation, apoptosis, and response to hypoxia. OBJECTIVE: To assess STRA13 involvement in carcinogenesis and evaluate its diagnostic value. METHODS: A comprehensive analysis was undertaken of the endogenous protein expression in 389 normal and corresponding malignant specimens, using newly generated polyclonal antibodies. RESULTS: STRA13 was commonly expressed in epithelial cells of normal and neoplastic tissues where it was confined mostly to the nucleus. Intense cytoplasmic STRA13 immunoreactivity was characteristic of myoepithelial and differentiated squamous epithelial cells of all organ sites and their neoplastic counterparts, suggesting application of STRA13 as a myoepithelial cell marker. A distinctive apical granular cytoplasmic staining pattern observed in the pancreas and large intestine was retained in corresponding metastatic carcinomas, providing for identification of the primary sites of these disseminating tumours. In less differentiated tumours there was a tendency to lose the cytoplasmic staining or to switch to nuclear STRA13 staining. Analysis of STRA13, HIF-1alpha, and CAIX expression patterns in a large set of various tumours substantiated the association of STRA13 with HIF-1alpha expression and hypoxia in vivo. Investigation of the molecular mechanisms of STRA13 nucleo-cytoplasmic shuttling suggested that STRA13 employs nuclear import/export that utilises the NLS/NES motifs situated within the N-terminus and in the middle of the protein. CONCLUSIONS: STRA13 may serve as a marker for myoepithelial cells, for the degree of tumour differentiation, and for identification of the primary site of certain metastatic tumours. In combination with CAIX and CAXII markers, it may lead to a more accurate classification of all renal carcinomas.

Genetic changes in human adrenocortical carcinomas.

Recent studies have suggested that loss of heterozygosity at loci on the short arm of human chromosome 11 (11p) may be important in the pathogenesis of benign and malignant adrenal cortical tumors. To test this concept, adrenocortical carcinomas from nine patients and benign adrenal cortical lesions from eight patients were tested for loss of alleles at loci on human chromosomes 11, 13, and 17. All patients with adrenocortical carcinoma whose normal somatic tissues were heterozygous for a locus on chromosome 17p had lost alleles in the tumor. Four of six patients with adrenocortical carcinoma who were heterozygous for one or more alleles on chromosome 11p in normal tissues had lost 11p alleles in the tumor. Three of six patients with adrenocortical carcinoma showed loss of 13q alleles in the tumor. Loss of alleles on chromosomes 11p, 13q, and 17p was observed in primary tumors and metastases but not in adrenocortical adenomas or hyperplastic lesions of the adrenal cortex. One patient with adrenocortical carcinoma had a somatic mutation in the HRAS1 gene in the normal adrenal gland. The consistency of the genetic changes on chromosomes 11p, 13q, and 17p suggests that they are important in the pathogenesis of adrenocortical carcinoma.

Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression.

BACKGROUND: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. METHODS: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. RESULTS: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 64% of breast cancer lines, in 30% of primary NSCLCs, and in 49% of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P =.046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. CONCLUSION: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.

The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium.

We used overlapping and nested homozygous deletions, contig building, genomic sequencing, and physical and transcript mapping to further define a approximately 630-kb lung cancer homozygous deletion region harboring one or more tumor suppressor genes (TSGs) on chromosome 3p21.3. This location was identified through somatic genetic mapping in tumors, cancer cell lines, and premalignant lesions of the lung and breast, including the discovery of several homozygous deletions. The combination of molecular manual methods and computational predictions permitted us to detect, isolate, characterize, and annotate a set of 25 genes that likely constitute the complete set of protein-coding genes residing in this approximately 630-kb sequence. A subset of 19 of these genes was found within the deleted overlap region of approximately 370-kb. This region was further subdivided by a nesting 200-kb breast cancer homozygous deletion into two gene sets: 8 genes lying in the proximal approximately 120-kb segment and 11 genes lying in the distal approximately 250-kb segment. These 19 genes were analyzed extensively by computational methods and were tested by manual methods for loss of expression and mutations in lung cancers to identify candidate TSGs from within this group. Four genes showed loss-of-expression or reduced mRNA levels in non-small cell lung cancer (CACNA2D2/alpha2delta-2, SEMA3B [formerly SEMA(V), BLU, and HYAL1] or small cell lung cancer (SEMA3B, BLU, and HYAL1) cell lines. We found six of the genes to have two or more amino acid sequence-altering mutations including BLU, NPRL2/Gene21, FUS1, HYAL1, FUS2, and SEMA3B. However, none of the 19 genes tested for mutation showed a frequent (>10%) mutation rate in lung cancer samples. This led us to exclude several of the genes in the region as classical tumor suppressors for sporadic lung cancer. On the other hand, the putative lung cancer TSG in this location may either be inactivated by tumor-acquired promoter hypermethylation or belong to the novel class of haploinsufficient genes that predispose to cancer in a hemizygous (+/-) state but do not show a second mutation in the remaining wild-type allele in the tumor. We discuss the data in the context of novel and classic cancer gene models as applied to lung carcinogenesis. Further functional testing of the critical genes by gene transfer and gene disruption strategies should permit the identification of the putative lung cancer TSG(s), LUCA, Analysis of the approximately 630-kb sequence also provides an opportunity to probe and understand the genomic structure, evolution, and functional organization of this relatively gene-rich region.

Cellular proteins that bind the von Hippel-Lindau disease gene product: mapping of binding domains and the effect of missense mutations.

The von Hippel-Lindau disease (VHL) gene is a novel tumor suppressor gene that plays a role in the pathogenesis of renal cell carcinomas and hemangioblastomas of the central nervous system. To begin an evaluation of the biological functions of the VHL gene product (pVHL), we prepared bacterial fusion protein between glutathione S-transferase and wild-type or mutant pVHLs. The fusion proteins were used to identify cellular proteins that bind to pVHL in vitro. Monkey kidney cells transfected with wild-type or mutant VHL cDNAs were used to identify cellular proteins that bind to pVHL in vivo. Wild-type pVHL consistently bound two cellular proteins with apparent molecular masses of 10 and 14 kilodaltons that were designated p10 and p14, respectively. Mapping studies with a panel of VHL deletion mutant proteins demonstrated that p10 and p14 bound to a 32-amino acid peptide located in the carboxy terminal portion of pVHL. Missense mutation located within this 32-amino acid peptide abrogated the ability of the VHL protein to bind p10 and p14. Of 67 VHL families with identified germline mutations, 42 families had mutations predicted to affect the p10/p14-binding region. Maintenance of the integrity of the p10/p14-binding region appears to be essential for cellular growth regulation by pVHL.

Chromosome 3p deletions in head and neck carcinomas: statistical ascertainment of allelic loss.

Loss of function of tumor suppressor genes is important in the origin and progression of common adult tumors. Loss of heterozygosity indicating allelic loss has been used to detect chromosomal regions that harbor these genes. Using over 20 restriction fragment length polymorphism markers spaced throughout the entire length of chromosome 3p, we have generated 3p allelotypes for 18-26 head and neck squamous cell carcinoma cell lines. We then estimated the average heterozygosity over 19 loci for a random sample drawn from natural populations to be 7.80 and that for the tumor lines to be 1.65, indicating a gross reduction of heterozygosity, presumably due to allelic loss. Further comparison of per locus heterozygosity in normal and tumor DNAs showed which loci contributed to the general loss of heterozygosity. We showed that the commonly deleted region of 3p probably lies telomeric to D3S3 (3p14) and centromeric to RAF1 (3p25). This large region includes several putative tumor suppressor genes involved in multiple common tumor types of lung, breast, kidney, ovary, and cervix. The data demonstrate that chromosome 3p allelic loss is a common event in head and neck cancers and suggest that chromosome 3p tumor suppressor genes contribute to the pathogenesis of these tumors.

Molecular analysis of genetic changes in the origin and development of renal cell carcinoma.

Renal cell carcinoma has been characterized by an abnormality on the short arm of chromosome 3 which suggests the presence of a tumor suppressor gene at this location. In order to more precisely define the location of the renal cell carcinoma gene and to differentiate molecular changes occurring in early stages of renal neoplasia versus those occurring later in malignant progression, DNA from normal and tumor tissue from 60 patients with various stages of renal cell carcinoma was analyzed for loss of alleles at different chromosomal loci. In tumor tissue from 51 of 58 evaluable patients (88%) there was loss of heterozygosity at one or more of 10 loci tested on chromosome 3 independently of tumor stage. Analysis of the genotypes identified the distal portion of 3p bounded by D3S2 and D3S22 (3p21-26) as the region of the disease gene. In tumor tissue from patients with advanced renal cell carcinoma, we found loss of heterozygosity on chromosome 11p in 5 of 21 (24%), on chromosome 13 in 3 of 9 (33%), and on chromosome 17 in 2 of 19 (11%). We found no loss of heterozygosity at the loci on chromosomes 11, 13, or 17 in tumor tissue from patients with localized renal cell carcinoma (N = 5). These data suggest the existence of a tumor suppressor gene on chromosome 3p which may be essential to the genesis of sporadic renal cell carcinoma and that other tumor suppressor genes are associated with progression of this malignancy.