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Previous karyotypic studies have indicated a possible series of non-random chromosomal events involved in progression of melanoma. We sought to verify and augment this model of melanocyte tumorigenesis by studying allelic deletions of markers mapping to these regions in 30 matched pairs of melanoma and constitutional DNA samples. Polymorphic loci on chromosomes 1, 7, 10, 11, 17, and 21 were analyzed and data combined with those previously obtained for chromosome arms 6q and 9p in the same series of tumours. The most frequent and earliest deletions were found on 9p (57%) and 10q (32%). With the exception of one case, no sample had loss of markers on another chromosome without concomitant loss of markers on 9p or 10q. Losses on 6q were also a frequent (31%) and early event whereas losses of loci on distal 1p (22%) or 11q (26%) occurred only in metastatic melanomas. A "background" rate (0-17%) of allele loss was seen on chromosomes 7, 17, and 21. These data strongly support the previous model based on karyotypic findings in melanocytic lesions. However, we have been able to further, augment that model by delimiting the regions of loss on 10q, to that distal to D10S254, and on 1p, to between D1S243 and D1S160.

Germline mutations within the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and one of its targets, the cyclin dependent kinase 4 (CDK4) gene, have been identi®ed in a proportion of melanoma kindreds. In the case of CDK4, only one speci®c mutation, resulting in the substitution of a cysteine for an arginine at codon 24 (R24C), has been found to be associated with melanoma. We have previously reported the identi®cation of germline CDKN2A mutations in 7/18 Australian melanoma kindreds and the absence of the R24C CDK4 mutation in 21 families lacking evidence of a CDKN2A mutation. The current study represents an expansion of these eorts and includes a total of 48 melanoma families from Australia. All of these families have now been screened for mutations within CDKN2A and CDK4, as well as for mutations within the CDKN2A homolog and 9p21 neighbor, the CDKN2B gene, and the alternative exon 1 (E1b) of CDKN2A. Families lacking CDKN2A mutations, but positive for a polymorphism(s) within this gene, were further evaluated to determine if their disease was associated with transcriptional silencing of one CDKN2A allele. Overall, CDKN2A mutations were detected in 3/30 (10%) of the new kindreds. Two of these mutations have been observed previously: a 24 bp duplication at the 5' end of the gene and a G to C transversion in exon 2 resulting in an M53I substitution. A novel G to A transition in exon 2, resulting in a D108N substitution was also detected. Combined with our previous ®ndings, we have now detected germline CDKN2A mutations in 10/48 (21%) of our melanoma kindreds. In none of the`CDKN2A-negative' families was melanoma found to segregate with either an untranscribed CDKN2A allele, an R24C CDK4 mutation, a CDKN2B mutation, or an E1b mutation. The last three observations suggest that these other cell cycle control genes (or alternative gene products) are either not involved at all, or to any great extent, in melanoma predisposition.Keywords: CDKN2A; CDKN2B; CDK4; melanoma; familial; mutation The CDKN2A (or p16) gene is located on chromosome 9p21 within a region that has been found to be frequently deleted in sporadic melanomas (Fountain et al

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Cells from Burkitt lymphoma ( B L ) biopsies were examined for Epstein-Barr virus ( E B V)-associated antigens by complement fixation (CF) tests

Reports of substantial evidence for genetic linkage of schizophrenia to chromosome 1q were evaluated by genotyping 16 DNA markers across 107 centimorgans of this chromosome in a multicenter sample of 779 informative schizophrenia pedigrees. No significant evidence was observed for such linkage, nor for heterogeneity in allele sharing among the eight individual samples. Separate analyses of European-origin families, recessive models of inheritance, and families with larger numbers of affected cases also failed to produce significant evidence for linkage. If schizophrenia susceptibility genes are present on chromosome 1q, their population-wide genetic effects are likely to be small.

Karyotypic analysis, loss of somatic heterozygosity, microcell fusion and cDNA transfection studies have provided compelling evidence that at least one tumour suppressor gene for melanoma resides on chromosome 6. In an attempt to further define the regions to which these putative suppressor genes map, we have carried out loss of heterozygosity (LOH) studies on DNA from 25 fresh melanoma tumours for 9 simple tandem repeat (STR) polymorphism markers spanning chromosome 6. Four samples displayed LOH or homozygosity for all markers studied, indicating that they had lost one homologue of chromosome 6. An additional 3 samples showed LOH for all markers on 6q. Furthermore, 30 melanoma cell lines, for which there were no matching somatic DNA samples, were analyzed for hemizygosity of markers on 6q. One cell line had a homozygous deletion of all markers tested and a further 12 cell lines displayed only one allele for 3 or 4 contiguous markers, indicating that most, if not all of these samples were hemizygous for the region of 6q distal to D6S87. Overall, the rate of LOH on 6q in the 55 melanoma DNAs was 35%, and there were no losses of markers on 6p without concomitant loss of markers on 6q. Two of 5 samples derived from primary melanomas showed LOH, which indicates that LOH for the melanoma suppressor gene on 6q, which maps to a region that contains the SOD2 locus, is a frequent and early event in melanoma tumorigenesis.