A detailed deletion mapping of the short arm of chromosome 3 in sporadic renal cell carcinoma.

A detailed analysis of loss of heterozygosity in 40 sporadic renal cell carcinomas was performed by using 30 restriction fragment length polymorphism markers which were mapped on the short arm of chromosome 3. A total of 30 of 38 informative cases (79%) showed loss of heterozygosity at one or more loci. Two commonly deleted regions have been identified at 3p13-14.3 and 3p21.3. One of them (at 3p13-14.3) spans the breakpoint of the (3;8) translocation in hereditary renal cell carcinoma previously reported (A. J. Cohen et al., N. Engl. J. Med., 301:592-595, 1979). The second common region of deletion at chromosome 3p21.3 encompasses D3F15S2, at which a high incidence of loss of heterzygosity in renal cell carcinoma has been reported. In addition to the gene at 3p25 being responsible for the hereditary type of renal cell carcinoma in patients with von Hippel-Lindau disease, our results suggest that at least two tumor suppressor genes for sporadic renal cell carcinoma exist on the short arm of chromosome 3.     

Detailed deletion mapping of the short arm of chromosome 3 in small cell and non-small cell carcinoma of the lung

We constructed a detailed deletion map of the short arm of chromosome 3 (3p) for 55 lung cancer cases by using 17 restriction fragment length polymorphism (RFLP) probes. Initially, we examined 40 small cell lung cancer (SCLC) cases and found three regions of deletion at 3p25–26, 3p21.3 and 3p14-cen. suggesting the possibility of at least three different tumor-suppressor genes on 3p. In order to obtain more detailed deletion area, and to compare the pattern of 3p deletion, we also examined 15 non-small cell lung cancer (NSCLC) cases. Compared to NSCLC cases, most of SCLC cases have widespread deletion on 3p, suggesting multiple tumor-suppressor genes on 3p may be inactivated in this type of cancer. In 3p21.3 area, minimum overlapping area of deletion lays between two probes which are close to each other. These data will be useful to isolate the putative tumor-suppressor genes located on the chromosome 3p.     

Recurrent deletion of the short arm of chromosome 3 in human renal cell carcinoma: shift of the c-raf 1 locus

A cytogenetic study performed on 6 human renal cell carcinomas after short-term culture on extracellular matrix with serum-free medium showed aneuploidy without structural changes in 2 tumors and a rearrangement of the short arm of chromosome 3 in 4 tumors, including deletions and a translocation involving the 3p14 and 3p21 bands. Chromosomal in situ hybridization with a c-raf 1 probe demonstrated that in 2 renal cancers with del3(p14 or 21) the cellular oncogene had shifted from 3p25 to 3p14 as a result of an interstitial deletion.     

Frequent allelic imbalance and cytogenetic deletion on the short arm of chromosome 1 in nasopharyngeal carcinoma

Thelossofheterozygosity,whichgenerallyoccursonchromosome3pl4,3p2l-p26,llq,13qandsoon,iscurrentlyreportedtobeahighfrequencyeventinnasopharyngealcarcinoma[1-3].Severaltumor-associatedgeneshavebeenclonedfromtheshort-armofchromosome1,whichhasbeenapprovedtoberelatedtotheoccurrenceanddevelopmentofmanytumors[4].ThoughourpreviousresultsofCGH[5-7]andFISHsuggestedtheexistenceofstructuralabnormality(mainlyasdeletion)ontheshortarmofchromosome1innasopharyngealcarcinoma,theextensionandfrequencyofthisabnor…     

Deletion mapping on the short arm of chromosome 1 in Merkel cell carcinoma

Twenty-two Merkel cell carcinoma (MCC) biopsies and six cell lines from 24 patients were examined for loss of heterozygosity (LOH) at 11 loci on 1p and one on 1q, to determine LOH regions on chromosome 1p. Sixteen (73%) tumors had LOH for at least one locus; 14 demonstrated LOH at more than one locus, and 7 (29%) samples had more than one region of loss, with 4 of these having loss at all informative loci on 1p. Three common regions of loss (SRO) were defined by LOH in multiple tumors. Eight samples demonstrated LOH between D1S214 and D1S160 (1p36), seven between D1S234 and D1S186 (1p35), and 11 for the region centromeric of D1S211 and D1S220 (1p32-1p33). Seven samples (29%) demonstrated more than one region of loss. LOH on 1p occurs frequently in MCC and more than one tumor suppressor gene on 1p is likely to play a role in the development of this tumor type.     

Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours

Wilms' tumour is one of the most common solid tumours of childhood. 11p13 (WT1 locus) and 11p15.5 (WT2 locus) are known to have genetic or epigenetic aberrations in these tumours. In Wilms' tumours, mutation of the Wilms tumour 1 (WT1) gene at the WT1 locus has been reported, and the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and KIP2/LIT1, can undergo maternal deletion or alterations associated with imprinting. Although these alterations have been identified in many studies, it is still not clear how frequently combined genetic and epigenetic alterations of these loci are involved in Wilms' tumours or how these alterations occur. To answer both questions, we performed genetic and epigenetic analyses of these loci, together with an additional gene, CTNNB1, in 35 sporadic Wilms' tumours. Loss of heterozygosity of 11p15.5 and loss of imprinting of IGF2 were the most frequent genetic (29%) and epigenetic (40%) alterations in Wilms' tumours, respectively. In total, 83% of the tumours had at least one alteration at 11p15.5 and/or 11p13. One-third of the tumours had alterations at multiple loci. Our results suggest that chromosome 11p is not only genetically but also epigenetically critical for the majority of Wilms' tumours.     

Loss of heterozygosity on chromosome 16 in sporadic Wilms' tumour.

To establish whether loss of heterozygosity (LOH) for chromosome 16q in Wilms'' tumours confers an adverse prognosis, DNA from 40 Wilms'' tumour/normal pairs were analysed using highly polymorphic microsatellite markers along the length of 16q. Fifteen per cent of tumours showed LOH for 16q. Although the common region of allele loss spanned the 16q24-qter region, a second distinct region of LOH was identified in 16q21. Five out of six tumours showing LOH were either (1) high stage or (2) low stage with unfavourable histology. In addition, there was a higher mortality rate in patients showing LOH for 16q than those that did not. These data strongly support the suggestion that LOH for 16q is associated with an adverse prognosis.     

Interstitial deletion of the short arm of chromosome 6 as a new cytogenetic marker of T-cell lymphoma

Three patients with malignant lymphoma, two of T-cell type and the other probably also of T-cell type, had an interstitial deletion of the short arm of chromosome 6, del (6)(p21p23), in common in their lymphoma cells. These findings suggest that this new type of chromosome deletion may be a specific marker for T-cell lymphoma and may play an important role in the lymphomagenesis and the expression of the T-cell phenotype.     

A myelodysplastic syndrome with eosinophilia associated with a break in the short arm of chromosome 16

A case is reported of a young man with cardiomyopathy and myelodysplasia with bone marrow and peripheral blood eosinophilia. Cytogenetic investigation revealed a (5;16) (q33;p13) translocation. This is the first report of myelodysplasia with eosinophilia associated with a break in 16p13 alone, with no abnormality of 16q22.     

Allelic loss on the short arm of chromosome 8 in oral squamous cell carcinoma.

Allelic deletions on the short arm of chromosome 8 (8p) are frequent events in many different types of malignant tumors, including head and neck tumors and oropharyngeal cancers. These regions are thought to harbor tumor suppressor genes. However, there has been no detailed analysis of loss of heterozygosity (LOH) on the chromosome arm 8p in oral squamous cell carcinoma (SCC). In order to estimate details of 8p loci involved in oral SCC, 32 patients with oral SCCs were examined for the LOH state 8p by PCR-LOH assay using 14 microsatellite markers. Based on our results a detailed deletion map of 8p showed LOH in at least one of the loci tested in 62.5% (20 of 32) of patients; and microsatellite instability (MI) was observed in 50% (16 of 32). The frequent LOH on this chromosome arm was identified at D8S87 and D8S258, mapped on 8p12 and 8p22, respectively. Fisher's exact test revealed no significant statistical correlation between the incidence of LOH or MI and clinicopathological features. Our observations indicate that the short arm of chromosome 8 may play a role in the pathogenesis of oral SCC; and that the two loci identified in this study may be tumor suppressor gene loci on 8p.     

Loss of heterozygosity in Wilms' tumour involves two distinct regions of chromosome 11

Pairs of tumour and normal DNA samples from 38 Wilms' tumour patients have been investigated for loss of heterozygosity using 12 probes from chromosome 11. Allele loss was detected in only 11 cases (31%). Densitometric analysis showed that allele loss was not due to non-disjunction or hemizygous deletion, but rather to mitotic recombination or non-disjunction plus reduplication. Although the development of homozygosity sometimes involved the whole of the short arm of chromosome 11, in a few tumours allele loss was restricted to band 11p15 or 11p13 and distal sequences. This suggests mutations in two distinct regions play an important role in Wilms' tumorigenesis. There was no apparent correlation between loss of heterozygosity and tumour stage, age of presentation, or prior exposure to chemotherapy.     

Frequent chromosome arm 13q deletion in aggressive non-Hodgkin's lymphoma.

To clarify the role of allelic loss on chromosome arm 13q in lymphomagenesis, we performed fluorescence in situ hybridization (FISH) analysis of a total of 43 primary lymphomas, including both indolent and aggressive non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD), using the specific probes at RB1 and D13S319 loci on the centromeric portion of chromosome arm 13q. Monosomy at either or both RB1 and D13S319 loci was detected in 15 of 43 (35%) lymphomas (14 of 43 cases at RB1 locus and seven of 43 cases at D13S319 locus); the 13q deletion was frequently detected in the aggressive NHLs (40%; 12 of 30 cases) compared with that in indolent NHL (17%; one of six cases) and a subset of HD (29%; two of seven cases). There are only six cases of 43 which have total monosomy 13q14, all aggressive NHL, 14% of total or 20% of this subgroup. In addition, we analyzed the loss of heterozygosity in 15 of the 43 primary lymphoma samples for several polymorphic microsatellite loci (D13S168, RB1 and D13S272) on the chromosome arm 13q, and confirmed the 13q deletion in four of five cases that were positive on FISH analysis. The subchromosomal region frequently altered in lymphoma on 13q14 is the region around RB1 locus and centromeric to D13S319 locus, which is an overlapped region frequently deleted in chronic lymphocytic leukemia. Together, our data indicate that the 13q alterations are present in a variety of types of lymphoma and occur in a significant proportion of aggressive NHLs, suggesting the possible presence of common candidate gene(s) on the 13q14 region, whose alteration may play an important role in the formation or development of a wide variety of mature lymphoid malignancies.     

Survival of children with Wilms' tumour in Europe

A total 2535 cases of Wilms' tumours registered in children aged 0--14 years by 34 population-based cancer registries in 16 countries of Europe in 1978--1992 and followed-up until the end of 1994 were included in this EUROCARE study. Overall 5-year observed survival of all children diagnosed in 1985--1989 was 83%, 95% confidence interval (CI) 80--85. Relatively large differences were observed between the European countries, with significantly lower survival of patients registered in the formerly socialist countries, Estonia, Poland and Slovakia. Overall European survival was slightly lower in comparison with results reported from the USA and Australia, which demonstrate a potential for improvement. Over the study period, overall survival adjusted for age, sex and country has increased significantly. This favourable trend is attributed primarily to improvements in treatment, particularly to the introduction of new chemotherapeutic agents.     

Efficient immortalization by SV40 T DNA of skin fibroblasts from patients with Wilms' tumor associated with chromosome 11p deletion

We report that transfection with a plasmid containing the SV40 early region (T) leads to a very high frequency of immortalization in two different strains of human diploid fibroblasts, each with a partial deletion of the short arm of chromosome 11. Immortalization often occurred without a recognizable "crisis" phase. Preimmortal cells showed a high frequency of spontaneous mutations and chromosomal aberrations. These results suggest that a gene involved in the control of senescence of human cells in vitro may be associated with this chromosome.     

Homozygosity of the short arm of chromosome 17 in cervical carcinoma.

We have determined the frequency of heterozygosity of the short arm of chromosome 17 in 20 cervical tumours using the highly polymorphic probe pYNZ22. Only 25% of the tumours were heterozygous at this locus. This is significantly lower than the level of 86% heterozygosity for this locus in the general population indicating that loss of one allele occurs in cervical cancer. Heterozygosity for a locus on the long arm of the same chromosome showed no significant difference between the tumours and the general population indicating that genetic loss was confined to the short arm of the chromosome. The analysis of premalignant lesions showed 70% of patients were heterozygous suggesting that loss of material from the short arm of chromosome 17 took place at a late stage in tumour development. This report confirms predictions made from previous karyotypic analysis and is the first indication of allele loss on the short arm of chromosome 17 in cervical cancer.     

Detailed deletion mapping on the short arm of chromosome-3 in nasopharyngeal carcinomas

Allelic loss on the short arm of chromosome 3 is one of the most consistent molecular genetic alterations observed in primary nasopharyngeal carcinoma (NPC). Detailed mapping of the region of common deletion on chromosome 3p will help to locate the site of candidate tumor suppressor gene(s) involved in the pathogenesis of NPC. We have examined allelic deletion in 27 primary undifferentiated NPC at 11 chromosomal loci (spanning from 3p13-3p25) using microsatellite polymorphic markers. Allelic loss was observed in 18 of 27 primary tumors (67%) when comparing tumor DNA with normal constitutional DNA of the same patient. Among these 18 cases, 10 showed allelic loss in all informative loci of chromosome 3p and 8 showed partial or interstitial deletion, The highest frequency of allelic loss was found in three loci, D3S1038 (52%), D3S1228 (50%) and D3S659 (50%). In 5 of the 8 cases with partial deletion of chromosome 3p, a common deletion region within 3p13 to 3p14.3, flanked by two loci, D3S1079 (3p13) proximally and D3S1228 (3p14.1-14.3) distally, was identified. These results suggest strongly the presence of tumor suppressor gene(s) within the 3p13 to 3p14.3 region, the deletion of which represent a critical event in the development of NPC. In the remaining 3 cases with partial chromosomal deletion, the pattern of allelic loss suggests the presence of two other regions of deletion distal to the commonly deleted region (3p13-14.3) identified. The presence of multiple deleted regions on chromosome 3p in NPC suggests that more than one tumor suppressor gene on 3p may be involved in the development of NPC.     

Isochromosome of the short arm of chromosome 12: clinically useful markers for male germ cell tumors

Twenty-nine tumor specimens were obtained from 24 males with germ cell tumors. All primary sites and histologies were represented. An isochromosome of the short arm of chromosome 12 [i (12p)] was found in 20 specimens obtained from 16 patients, a 46,XY normal karyotype was present in seven specimens, and one specimen was a cytogenetic failure. The i(12p) was found in tumors from all primary sites and in all histologies, including a choriocarcinoma. The presence of three or more additional copies of 12p was associated with a statistically significant greater likelihood of treatment failure. With diagnostic and possibly prognostic importance in germ cell tumors in males, the high frequency of i(12p) in our series of studies and in those of others indicates that it probably occurs as a very early defect in the development of these tumors. Further studies of chromosome 12 in males with these tumors are warranted.