A family with spinal anaplastic ependymoma: evidence of loss of chromosome 22q in tumor

Familial ependymal tumors are a very rare disease, the pathogenesis of which is unknown. Previous studies indicate an involvement of tumor suppressor genes localized within chromosomal region 22q, whereas details are still unclear. Here we report a non-neurofibromatosis type-2 (non-NF2) Japanese family in which two of the four members are affected with cervical spinal cord ependymoma, and one of the four is affected with schwannoma. Loss of heterozygosity (LOH) studies were carried out searching for common allelic loss at chromosomal region 22q11.2-qtel in two of the affected patients. Our findings support a prediction for existence of a tumor suppressor gene on chromosome 22 especially related to the tumorigenesis of familial ependymal tumors.     

Ring chromosome 22 and neurofibromatosis type II: proof of two-hit model for the loss of the NF2 gene in the development of meningioma

Carriers of a ring chromosome 22 are mentally retarded and show variable facial dysmorphism. They may also present with features of neurofibromatosis type II (NF2) such as vestibular schwannomas and multiple meningiomas. In these cases, tumourigenesis has been suspected to be caused by the loss of both alleles of the NF2 gene, a tumour suppressor localized in 22q12.2. Here, we describe an 18-year-old patient with constitutional ring chromosome 22 and mental retardation who developed rapid-onset spastic paraparesis at the age of 15 years. The causative spinal meningioma at the level of T3, which compressed the spinal cord, was surgically removed, and the patient regained ambulation. Array comparative genomic hybridization (array CGH) and multiplex ligation-dependent probe amplification (MLPA) analyses in blood revealed a terminal deletion in 22q13.32, not comprising the NF2 gene. In tumour tissue, loss of the whole ring chromosome 22 including one NF2 gene due to mitotic instability constituted the likely first hit, while a point mutation in the other allele of the NF2 gene (c.784C>T, p.R262X) was shown as second hit. We review all cases from the literature and suggest clinical guidelines for surveillance of patients with ring chromosome 22.     

Correlation of loss of heterozygosity at chromosome 9q with histological subtype in medulloblastomas.

Patients with the nevoid basal cell carcinoma syndrome (NBCCS) are at increased risk for medulloblastomas as well as for basal cell carcinomas. The gene for NBCCS has been mapped to chromosome 9q22.3-q31 by linkage analysis, and loss of heterozygosity (LOH) in this region has been demonstrated in approximately one-half of sporadic basal cell carcinomas. In the present study, LOH for chromosome 9q22.3-q31 microsatellite markers was investigated in medulloblastomas occurring among children with NBCCS and in sporadic medulloblastomas. Histologically, all 3 NBCCS medulloblastomas were noted to have a desmoplastic phenotype, and LOH was detected in both of the 2 cases for which microsatellite markers were heterozygous in normal tissues. LOH was also detected in a subset of sporadic medulloblastomas, each of which were found to display the desmoplastic phenotype. In all, 3 of the 6 sporadic desmoplastic tumors showed LOH, whereas LOH was not seen in any of the 11 sporadic, non-desmoplastic medulloblastomas studied. Additionally, desmoplastic tumors lacking detectable LOH each showed histological features of so-called cerebellar neuroblastoma, a subgroup of desmoplastic medulloblastoma with extensive neuroblastomatous differentiation. The data are consistent with a role for inactivation of a tumor suppressor gene at chromosome 9q in the development of medulloblastomas in patients with NBCCS and of sporadic medulloblastomas characterized by a desmoplastic phenotype similar to that found in patients with NBCCS. Restriction of chromosome 9q loss to non-neuroblastomatous desmoplastic tumors suggests that this variant of medulloblastoma maybe pathogenetically distinct from tumors having other histological phenotypes.     

Clinical significance of chromosome 1p/19q loss of heterozygosity and Sox17 expression in oligodendrogliomas

Objective: To study chromosome 1p/19q loss of heterozygosity (LOH) and Sox17 protein expression in oligodendrogliomas and correlate this loss with clinicopathological features. Methods: This study included 100 cases of oligodendrogliomas at the First Affiliated Hospital of Xinjiang Medical University from 2003 to 2014. The cases included paraffin-embedded tissues from 50 low-grade oligodendrogliomas and 50 anaplastic oligodendrogliomas. Chromosome 1p/19q LOH was detected by fluorescence in situ hybridization (FISH) and Sox17 protein expression was analyzed by immunohistochemistry. Clinicopathological characteristics of the oligodendrogliomas were compared and prognosis analyzed using Cox regression and Kaplan-Meier analyses. Results: The LOH positivity rate of 1p/19q was 52% in 50 cases of low-grade oligodendrogliomas and 68% in 50 cases of anaplastic oligodendrogliomas (P = 0.102). The rates of Sox17 expression were significantly different in oligodendrogliomas (82%) and anaplastic oligodendrogliomas (62%, P = 0.026). Single factor analysis determined that 1p/19q LOH (P = 0.000), Sox17 protein expression (P = 0.000), location (P = 0.001), chemotherapy (P = 0.000), and radiation therapy (P = 0.001) were associated with oligodendroglioma patient prognosis. Cox multiple factors regression analysis determined that 1p/19q LOH and Sox17 expression were independent prognostic factors of oligodendrogliomas. Conclusion: In this study, oligodendroglioma patients with 1p/19q LOH and Sox17 protein expression had a better prognosis. Thus, analysis of 1p/19q LOH and Sox17 protein expression could significantly enhance diagnostic accuracy, guide treatment, and improve the prognosis.     

Hypermethylation and Transcriptional Downregulation of the TIMP3 Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

The gene for the tissue inhibitor of metalloproteinase 3 (TIMP3) on 22q12.3 had been reported to be inactivated by promoter methylation in various types of cancers, with controversial findings in meningiomas. We performed direct sodium bisulfite sequencing in a series of 50 meningiomas, including 27 benign meningiomas [World Health Organization (WHO) grade I], 11 atypical meningiomas (WHO grade II) and 12 anaplastic meningiomas (WHO grade III), and found hypermethylation of TIMP3 in 67% of anaplastic meningiomas, but only 22% of atypical and 17% of benign meningiomas. Moreover, TIMP3 methylation scores were significantly inversely correlated with TIMP3 mRNA expression levels (P = 0.0123), and treatment of the meningioma cell line Ben‐Men‐1 with demethylating agents induced an increased TIMP3 mRNA expression. TIMP3 is located in the chromosomal band 22q12, the allelic loss of which occurs early in meningioma tumorigenesis and preferentially targets the NF2 tumor suppressor gene. In our tumor panel, all meningiomas with TIMP3 hypermethylation—except for a single case—exhibited allelic losses on 22q12.3. Thus, TIMP3 inactivation by methylation seems fairly exclusive to meningiomas with allelic losses on 22q12 but—in contrast to NF2 mutation—appears to be involved in meningioma progression as it is associated with a more aggressive, high‐grade meningioma phenotype.     

Loss of heterozygosity for chromosome 22 DNA sequences in human meningioma.

Monosomy of chromosome 22 in meningioma was the first consistent cytogenetic anomaly reported for a solid tumor. Although most meningiomas are isolated sporadic lesions, multiple and familial occurrences have been reported, usually in cases of documented neurofibromatosis 2 (NF2). Previous reports have placed the NF2 locus on chromosome 22, flanked by the markers D22S1 and D22S28. We report a restriction fragment-length polymorphism study of 16 meningiomas conducted using chromosome 22 probes. None of the patients had clinical findings or a family history of NF2, although two of them eventually developed multiple intracranial meningiomas. Detectable loss of chromosome 22 sequences was observed in 50% of informative patients. Deletion mapping of tumors with preserved sequences showed that the loss of chromosome 22 DNA overlapped the region previously linked to NF2, but also included a sequence distal to the NF2 locus. These results suggest that the oncogenesis of human meningioma involves inactivation of a chromosome 22 locus that may be in close proximity to the gene for NF2.     

Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: Importance of copy neutral LOH

Dermal neurofibromas (dNFs) are benign tumors of the peripheral nervous system typically associated with Neurofibromatosis type 1 (NF1) patients. Genes controlling the integrity of the DNA are likely to influence the number of neurofibromas developed because dNFs are caused by somatic mutational inactivation of the NF1 gene, frequently evidenced by loss of heterozygosity (LOH). We performed a comprehensive analysis of the prevalence and mechanisms of LOH in dNFs. Our study included 518 dNFs from 113 patients. LOH was detected in 25% of the dNFs (N = 129). The most frequent mechanism causing LOH was mitotic recombination, which was observed in 62% of LOH‐tumors (N = 80), and which does not reduce the number of NF1 gene copies. All events were generated by a single crossover located between the centromere and the NF1 gene, resulting in isodisomy of 17q. LOH due to the loss of the NF1 gene accounted for a 38% of dNFs with LOH (N = 49), with deletions ranging in size from ～80 kb to ～8 Mb within 17q. In one tumor we identified the first example of a neurofibroma‐associated second‐hit type‐2 NF1 deletion. Analysis of the prevalence of mechanisms causing LOH in dNFs in individual patients (possibly under genetic control) will elucidate whether there exist interindividual variation. Hum Mutat 32:78–90, 2011. © 2010 Wiley‐Liss, Inc.     

Differential loss of heterozygosity profile on chromosome 3p in ductal and lobular breast carcinomas

The 2 main histologic types of infiltrating breast cancer, invasive lobular and invasive ductal carcinoma, are morphologically and clinically distinct. Studies revealed that different patterns of gene expression and loss of heterozygosity can also distinguish these 2 subtypes. A whole-genome study using single nucleotide polymorphism array found a significantly higher frequency of loss of heterozygosity on 3p in invasive ductal carcinoma when compared with invasive lobular carcinoma. In this study, we performed a loss of heterozygosity analysis of the 3p chromosome region in ductal and lobular breast tumors. Seven microsatellite markers were evaluated in a series of 136 sporadic breast cancer cases (118 invasive ductal carcinoma and 18 invasive lobular carcinoma) and correlated with clinical-histopathologic parameters from the patients. A significantly higher frequency of loss of heterozygosity was observed in invasive ductal carcinoma (65.3%) when compared with invasive lobular carcinoma (38.9%). When the markers were analyzed separately, loss of heterozygosity at 3 of them, D3S1307 in 3p26.3, D3S1286 in 3p24.3, and D3S1300 in 3p14.2, were significantly more frequent in ductal than in lobular tumors. D3S1307 marker showed the highest frequency of loss of heterozygosity in invasive ductal carcinoma (46.2%), and associations between loss of this marker and loss of estrogen and progesterone receptors were found in these samples. Our results confirm the observations that invasive ductal carcinoma has a higher frequency of loss of heterozygosity events across the 3p region than invasive lobular carcinoma and show that specific losses on 3p26.3, 3p24.3, and 3p14.2 regions are more frequent in ductal than in lobular tumors. We discuss our data in relation to the known tumor suppressor genes that are mapped at the 3p loci investigated and their present relevant roles in breast cancer.     

Frequent loss of heterozygosity on chromosome 12q in non-small-cell lung carcinomas

Chromosomal aberrations in non-small-cell lung carcinomas (NSCLCs) are common events. In our study, the lung cancer cell lines (NCI-H446 and SPC-A-1) displayed numerous numerical and structural alterations in their chromosomes by G-banded karyotypic analysis, and abnormalities of chromosome 12 by fluorescence in situ hybridization. Sequentially, we used 14 microsatellite markers within 12q to analyze loss of heterozygosity (LOH) in lung cancer cell lines and NSCLCs. Possible LOH on 12q were statistically inferred to occur in five lung cell lines. Importantly, 17 out of 25 NSCLCs (68%) showed LOH at chromosome 12q. Frequencies of LOH for individual markers ranged from 18% to 44%. Several deletions which were marked with D12S1301, D12S2196, D12S398, D12S90, D12S1056, D12S1713, D12S375, D12S1040, D12S326, and D12S106 were newly detected. Allelic loss on 12q15–q21 detected with D12S1040 occurred at the later stages of NSCLC progression (p < 0.05, Fisher’s exact test). LOH on 12q marked with D12S2196, D12S398, D12S326, and D12S106 were frequently found in NSCLCs from the patients without smoking history (p < 0.05, Fisher’s exact test). These findings indicated that allelic loss on 12q is commonly involved in NSCLCs, and new tumor suppressor genes may occur within 12q.     

Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas

Meningiomas are usually benign tumors; however, they can recur after surgical resection and occasionally show histological progression to a higher malignancy grade. Five such rare cases of aggressively recurring meningiomas were present in our departmental cohort of 923 primary meningeal neoplasms operated over a 17-year period. Four other aggressively recurring meningeal tumors with a very similar clinical and histomorphological appearance (three undifferentiated meningeal sarcomas, one hemangiopericytoma) were also included in this study. We investigated whether disease progression can be traced by genetic alterations and whether a pattern of genetic alterations is specific for meningiomas. A total of 40 specimens from primary tumors and multiple recurrences of the nine patients were analyzed with 26 polymorphic allelic markers for deletions on 1p, 1q, 9q, 10q, 14q, and 22q. Loss of heterozygosity (LOH) at 22q was observed in all meningiomas cases at the earliest time point analyzed. Allelic loss at 1p was seen in the original tumor in two cases and upon meningioma recurrence in two others. Deletion on 10q occurred during tumor progression in two cases, and on 9q and 14q in one case. While allelic loss at 22q appears to be an early event in aggressive meningioma disease, there is a clear correlation of further deletions on chromosome arms 1p, 9q, 10q, and 14q with histopathological and clinical progression, as shown in these intraindividual trackings. None of these genetic findings were present in the non-meningiomatous meningeal tumors, indicating that meningothelial cells have their own lineage-specific genetic pathways towards clinical malignancy.     

Loss of heterozygosity reveals non-VHL allelic loss in hemangioblastomas at 22q13

Hemangioblastomas (HBs) are low-grade (World Health Organization grade I/IV) central nervous system (CNS) tumors that frequently contain VHL (3p26) mutations. They occur sporadically and in von Hippel Lindau (VHL) disease. Encoded pVHL aids degradation of hypoxia-inducible factors (HIFs) in the presence of normal oxygen levels. HBs provide an in vivo view of HIF effects within a CNS tumor. Typically, HBs are cystic tumors containing a mural nodule formed by noninvasive, vacuolated stromal cells that are embedded in a network of capillaries. Nine HBs, consecutively resected from 8 patients at our institution during a recent 2-year time span, were evaluated for additional losses of tumor suppressor genes. Non-VHL microsatellites studied for loss of heterozygosity (LOH) are near tumor suppressor genes lost in gliomas, pituitary adenomas, several CNS tumors on 22q, neurofibromatosis 1, and colon carcinomas (13, 2, 2, 1, and 2 markers for each, respectively). LOH in the region of 3p21.3-3p26.3 occurred in 3 of 8 HBs informative for at least 1 marker (D3S1539, D3S2303, or D3S2373). By using 2 markers (D22S417 and D22S532) for 22q13.2, LOH was found in 5 of 8 informative HBs. All 3 HBs with allelic losses near VHL also showed LOH at 22q13.2. No consistent losses were found with markers for 1p34, LMYC, 5q21, 5q32, 9p21, 10q23, 17p13, and 19q13. LOH for the 22q13.2 region in HBs suggests that the loss of another tumor suppressor gene is involved in the pathogenesis of HBs in addition to VHL. Absence of LOH for glioma markers is consistent with the low-grade behavior of HBs.     

Clonal selection of adenocarcinoma of the lung as determined by loss of heterozygosity

Although the most frequently altered oncogenes and tumor suppressor genes in non-small cell lung carcinoma (NSCLC) have been recognized, the exact mechanisms responsible for the progression and phenotypic expression of carcinoma, particularly adenocarcinoma of the lung are uncertain. Fifty-six cases of adenocarcinoma of the lung (11 bronchioloalveolar carcinoma [BAC], 25 stage 1, 20 stage 2) and paired 19 lymph node metastases (LNM) of stage 2 adenocarcinomas were analyzed for loss of heterozygosity (LOH). Analysis included a panel of 14 polymorphic microsatellite markers located on 1p, 3p, 5q, 9p, 10q, and 17p. LOH on chromosomes 1p (P = 0.0209) and 17p (P = 0.0274) was more frequently present in stage 1 adenocarcinomas than in BAC. There was no significant difference between BAC, stage 1 and stage 2 adenocarcinoma in the frequency of LOH at individual chromosomal arms. The pattern of LOH in LNM of stage 2 adenocarcinoma was similar to the primary tumor. Overall fractional allelic loss (FAL) was significantly different between BAC and stage 1 invasive adenocarcinoma (P = 0.0013), and it was significantly higher in stage 1 adenocarcinoma than in stage 2 adenocarcinoma (P = 0.0062) and their LNM (P = 0.0001). Stage 2 adenocarcinomas showed significantly higher overall FAL than their LNM (P = 0.022). Our study failed to identify a single target gene responsible for progression of lung adenocarcinoma. A trend towards lower overall FAL in advanced stage tumors and in their metastases suggests that clonal selection may play a role in lung adenocarcinoma progression.     

NF2 status of meningiomas is associated with tumour localization and histology.

In approximately 60% of sporadic meningiomas, the tumour suppressor gene NF2, located on chromosome 22q, is inactivated. Mutations in the NF2 gene have been specifically reported in transitional and fibrous, but not meningothelial, meningiomas. Since meningothelial meningiomas frequently occur in anterior parts of the skull base, the association between tumour localization, size, histological subtype and NF2 status was investigated in a group of 42 sporadic meningiomas. NF2 status was determined by LOH analysis, karyotyping and FISH. Tumour size and site were evaluated by CT scans and MRIs. A strong correlation between tumour localization in the anterior skull base and intact 22q was revealed (p=0.003). On the other hand, tumour localization at the convexity was associated with disruption of NF2 (p=0.023). Furthermore, an association between chromosome 22 status and histological subtype was observed: abnormalities of chromosome 22q were more frequent in transitional and fibrous meningiomas than in the meningothelial variant (p<0.001). Also, the meningothelial meningiomas were more often located in the anterior skull base (p<0.006). Based on these findings, it is concluded that an alternative histogenesis and genetic pathway is likely to exist for meningiomas arising in the anterior skull base.     

Definition of a region of loss of heterozygosity at chromosome 11q in cervical carcinoma.

Chromosomal deletions at segment 11q23-q24 have been identified in a variety of human epithelial tumors, including cervical carcinoma (CC), indicating the presence in this region of at least a tumor suppressor gene (TSG) involved in the development of these neoplasms. To localize the 11q deletion target more precisely, 54 primary cervical carcinomas were examined for loss of heterozygosity (LOH) using a panel of microsatellite DNA markers mapping to 11p.15 and spanning region 11q23-qter. Nineteen tumors were found to have LOH at chromosome 11q. The highest frequency of LOH was observed at locus APOC-3, located in 11q23.1-q23.2, which was deleted in 42% of the informative cases. In contrast, LOH was infrequent at distal 11q in current series of CC. The smallest common region of loss included APOC-3 and was defined distally by marker D11S925 in region 11q23. The present data strongly suggest that the 11q suppressor gene(s) involved in cervical tumorigenesis is likely to be located at chromosome region 11q22-q23.     

Detection of loss of heterozygosity on chromosome 9q22.3 in microdissected sporadic basal cell carcinoma

Identification of loss of heterozygosity (LOH) at specific genetic loci in cancer cells suggests the presence of a tumor suppressor gene within the deleted region. A basal cell carcinoma (BCC) susceptibility gene, human homolog of drosophila patched (PTC), has been recently cloned and localized on chromosome 9q22.3. Mutation and deletion of this region has been reported in BCCs using frozen tumor tissue. The objective of this study was to test whether LOH of human PTC on chromosome 9q22 could be detected in archival sporadic BCCs. We studied 20 randomly selected sporadic BCCs by microdissection and polymerase chain reaction using paraffin-embedded, formalin-fixed material on glass slides. In all cases, analysis was performed with the polymorphic markers D9S53, D9S15, D9S287, and D9S303. The LOH frequencies were 30%, 42%, 56%, and 75% with D9S15, D9S287, D9S53, and D9S303, respectively. LOH at 9q22 was identified in 12 of 20 cases (60%) with at least one marker. Seven cases showed LOH with two markers, two cases with three markers, and one case showed LOH with all four markers. The results indicate that BCC LOH can be frequently identified in paraffin-embedded BCC after routine processing.     

Ventricular septal defect associated with microdeletions of chromosome 22q11.2

Microdeletions of chromosome 22q11.2 (del.22q11) cause DiGeorge syndrome, velo-cardio-facial syndrome, and conotruncal anomaly face syndrome, which are commonly associated with conotruncal heart anomalies. Approximately 15% of the patients manifest ventricular septal defect (VSD), and the conal septal type of VSD has been proposed to be associated with del.22q11, since it is categorized as a conotruncal anomaly. However, the types of VSD associated with del.22q11 remain poorly studied. The purpose of this study is to assess whether conal septal VSD or other types of VSDs are associated with del.22q11. We analyzed the chromosomes of 22 consecutive patients with conal-septal VSD, prospectively, and evaluated the types of VSD observed in 3 patients with del.22q11, retrospectively. Del.22q11 was not detected in any of the 22 patients with conal septal VSD. All the VSDs observed in the 3 patients with del.22q11 were a perimembranous type of VSD, which is not a conotruncal anomaly. Our results suggest that perimembranous VSD can be associated with del.22q11, but del.22q11 is not a common cause of conal-septal VSD.     

Extensive loss of heterozygosity accounts for differential mutation rate on chromosome 17q in human lymphoblasts

In order to investigate the influence of loss of heterozygosity(LOH) events on mutation rate, we studied two closely relatedhuman lymphoblastoid cell lines, AHH-1 (h2E1.v2) and MCL-5,which are heterozygous at the tk locus (chromosome 17q23–25).Although they have similar mutant fractions at the hprt locus,the mutant fraction and rate at tk is four to five times higherin AHH-1. Analysis of 58 spontaneous TK-mutants from AHH-1 andMCL-5 showed that the occurrence of LOH events was more frequent(23/24) in AHH-1 than MCL-5 (16/34). A set of five microsatellitepolymorphism loci was used to map the extent of LOH along chromosome17q. In AHH-1 cells, 15/23 of the LOH events encompassed atleast 35% of the sex-averaged genetic length of chromosome 17q(98 cM). Additionally, the next most extensive category of LOHaccounted for 5/23 TK- mutants, and encompassed at least 17cM. In contrast, LOH events observed in MCL-5 are very restrictedin extent; only one LOH tract extended as far as 4 cM from tk.The higher mutation rate at tk in AHH-1 can, therefore, be entirelyattributed to the recovery of chromosomal scale LOH in viable,normal growth TK-mutants. Furthermore, these data demonstratethat the regional potential for LOH is likely to be an importantdeterminant of mutation rate for loci within that chromosomalsegment. ¹To whom correspondence should be addressed     

Frequent loss of heterozygosity at 6q in pheochromocytoma

Multiple genetic alterations have been associated with pheochromocytoma (PCC). Most PCCs are sporadic, but they also occur in inherited tumor syndromes, including von Hippel-Lindau disease. Although the etiology of most inherited PCCs is well documented, little is known about the etiology of sporadic tumors. Mutations of those genes that harbor germ-line mutations in familial cases cover only 10% to 15% of somatic mutations in sporadic PCCs. A previous cytogenetic analysis indicated frequent loss of 6q in sporadic PCCs. We therefore investigated in detail 18 PCCs using 22 microsatellite markers spanning 6q to search for the presence of allele deletions and identify specific regions likely to contain tumor suppressor genes involved in PCC. Moreover, we sought to compare PCC with capillary hemangioblastoma, another von Hippel-Lindau disease-associated tumor that we previously found to harbor frequent loss of heterozygosity (LOH) at 6q. Our study revealed a high frequency (13/18; 72%) of overall 6q LOH in PCCs. Loss of heterozygosity at 6q was observed in 6 benign (6/9; 67%) and 7 borderline (7/9; 78%) tumors. We identified 2 regions where LOH or allelic imbalance was common (ie, 6q14 [9/18; 50%] and 6q23-24 [6/18; 33%]). We further focused the search using markers specific for the ZAC1 gene region located at 6q24-25. Altogether, for all 6q23-25 markers, including the ZAC1-specific ones, LOH or allelic imbalance was observed in 50% (9/18) of the PCCs. Similar to our findings for capillary hemangioblastomas, our data for the first time suggest that one or several tumor suppressor genes located at 6q, particularly at 6q23-24, may play a role in the tumorigenesis of PCCs.     

Loss of heterozygosity at chromosomes 8p, 9p,and 14q is associated with stage and grade of non-papillary renal cell carcinomas

In this study, 105 non-papillary renal cell carcinomas (RCCs) have been examined for allelic loss at the chromosome 8p12–21.1, 9p21, and 14q24.2-qter regions, each by two highly polymorphic microsatellites. Loss of heterozygosity (LOH) was detected at both chromosome 8p and 9p in 33 per cent of the cases and at chromosome 14q in 45 per cent of the tumours. A correlation of variables such as size, grade, and stage of tumours with these specific genetic alterations showed that loss of chromosomes 8p and 9p, and especially loss of chromosome 14q regions, is significantly associated with a higher grade of tumour and the combined LOH at these chromosomal sites with advanced tumour stage. These genetic alterations did not show any correlation with the size of non-papillary RCCs. This study suggests that genetic markers at the above-mentioned chromosomal sites can predict the clinical outcome of non-papillary RCCs. © 1997 John Wiley & Sons, Ltd.