Closing in on the MEN2A Locus

The mapping of the locus for multiple endocrine neoplasia type 2A (MEN 2A) to chromosome 10 using linkage is briefly reviewed including a discussion of linkage strategy and reference to some of the exclusions before the assignment. The subsequent development of the map of the centromeric region of the chromosome and the linking of what appear to be the four closest flanking markers and the centromeric alphoid sequence to the disease locus are reviewed. To date no recombination has been observed between the centromeric marker and the MEN2A locus among, at least, 26 informative meioses, 11 of which are phase known. While no obligate recombination has been observed between the markers FNRB, D10S34, and RBP3 and the MEN2A locus in males, it has been observed in females and is as much as 10% for the marker RBP3. The sex difference in recombination frequency is significant. The four polymorphic flanking markers, FNRB, D10S34, RBP3, and D10S5, along with the centromeric marker D10Z1 will prove to be useful for management of the families with the disease. It will be possible in most families to give a very high (or low) probability for at risk members of the families and in some cases the DNA results will be virtually diagnostic

The molecular genetics of human brain tumors

A series of 13 benign and 27 malignant human gliomas was analysed to define the fundamental molecular genetic abnormalities underlying glioma development. Southern analysis of restriction fragment length polymorphisms was used to assess loss of chromosomal material in tumour DNA, an event compatible with dysfunction of putative tumour suppressor genes. Chromosomes 10, 13q and 17p were selected for study on the basis of previously described cytogenetic abnormalities in gliomas. In addition, the integrity of the retinoblastoma gene on chromosome 13q, as well as the putative tumour suppressor gene p53 on chromosome 17p, was assessed. Tumour DNA was also examined for amplification of the epidermal growth factor receptor (EGFR), N-mvc and c-erbB-2 oncogenes. The results indicated that specific molecular lesions were associated with increasing grades of malignancy. Thus, loss of genetic material on chromosome 17 was present in both benign and malignant gliomas, whereas loss of loci on chromosomes 10 and 13 was seen only in malignant gliomas. A structural abnormality of the retinoblastoma gene coding region was detected in one glioblastoma. Amplification of the EGFR oncogene was present in 5 malignant gliomas. In contrast to other tumours studied, only glioblastomas contained more than one molecular abnormality in the same tumour. The relevance of these findings to our understanding of the molecular mechanisms underlying tumour development and to their effect on improving the accuracy of tumour diagnosis are discussed. In a further set of experiments, the NIH3T3 transfection assay was used to reveal the presence of activated oncogenes in the genome of human cell lines thought to be derived from gliomas. One cell line contained an activated oncogene. This oncogene was identified, by oligonucleotide hybridisation to polymerase chain reaction-amplified DNA, as an N-ras gene with a codon 61 mutation. However, it was demonstrated by DNA fingerprinting that the supposed human glioma cell line had been previously contaminated with cells of rhabdomyosarcoma origin