Biomedical subjects
Publications and source records attributed to E Engel.
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The EORTC Melanoma Cooperative Group conducted a phase II trial (study number 18891) to study the effect of Toremifene in 45 patients with advanced, metastatic melanoma. Male and female patients, median age 61 (range 23-88) years received a mean total dose of 11 g (4.3-62.6) orally for at least 6 weeks. No objective remissions were seen. Four patients (3 women and 1 man; 9%) experienced 3-6 months' disease stabilization. The toxicity of the drug, given at a dose of 240 mg daily, was negligible. Because of the minimal side-effects, Toremifene may be recommended for patients who have only a small number of slowly growing metastases, in particular to soft tissue and lung.
We studied the mechanism of ring chromosome 21 (r(21)) formation in 13 patients (11 unique r(21)s), consisting of 7 from five families with familial r(21) and 6 with de novo r(21). The copy number of chromosome 21 sequences in the rings of these patients was determined by quantitative dosage analyses for 13 loci on 21q. Nine of 11 r(21)s, including the 5 familial r(21)s, showed no evidence for duplication of 21q sequences but did show molecular evidence of partial deletion of 21q. These data were consistent with the breakage and reunion of short- and long-arm regions to form the r(21), resulting in deletion of varying amounts of 21q22.1 to 21qter. The data from one individual who had a Down syndrome phenotype were consistent with asymmetric breakage and reunion of 21q sequences from an intermediate isochromosome or Robertsonian translocation chromosome as reported by Wong et al. Another patient, who also exhibited Down syndrome, showed evidence of a third mechanism of ring formation. The likely initial event was breakage and reunion of the short and long arms, resulting in a small r(21), followed by a sister-chromatid exchange resulting in a double-sized and symmetrically dicentric r(21). The phenotype of patients correlated well with the extent of deletion or duplication of chromosome 21 sequences. These data demonstrate three mechanisms of r(21) formation and show that the phenotype of r(21) patients varies with the extent of chromosome 21 monosomy or trisomy.
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The concept of uniparental disomy--the presence of a chromosome pair derived solely from one parent in a diploid offspring--was introduced in 1980 as a probable consequence of the high rate of germ cell aneuploidy in man, and has now been convincingly demonstrated through molecular analyses in several families. A most likely mechanism for the production of uniparental disomy is the chance reunion, and complementation, of 2 gametes aneuploid for the same chromosome member; uniparental disomy could also occur through other mechanisms including postzygotic non-segregation in a trisomic conceptus. Uniparental disomy may result in isodisomy, i.e., homozygosity of a series of contiguous alleles in a pair of homologues. The presence and degree of isodisomy in an offspring depend in turn on the occurrence, timing, and extent of the meiotic recombination that had occurred in the chromosome pair of the disomic gamete involved. Uniparental disomy with or without isodisomy can explain a number of unusual observations, such as the unexpected pattern of transmission of a genetic disorder. The two may be associated with an imprinting effect to produce pathological phenotypes, as has been observed in the mouse, and may be the basis for a number of syndromes of as yet unclear cause. The evidence for uniparental disomy, isodisomy, and imprinting in man is reviewed, and strategies for their detection presented.
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The author presents three potential ways of developing an university centre of medical genetics, to make most effective use of this fast-evolving discipline. The three possibilities discussed are: i) the attachment of genetics units to major departments; ii) the creation of a large autonomous genetics centre (be Department or Institute) fulfilling all the requirements of the hospital; and iii) an "ecumenical" approach, that is a main genetics centre with a very few associated, highly specialized, departmental satellite units. The author argues in favour of the last solution.
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We have analyzed genomic DNA sequences from 125 prospectively collected single unilateral primary breast carcinoma samples for the presence of alterations of c-myc, c-erbB-1, c-erbB-2, c-Ki-ras and c-Ha-ras protooncogenes. Amplification of the c-myc gene was found in 18% of the samples, and in one sample a non-germ line c-myc related DNA fragment or rearrangement was detected. We have found a significant association (P = 0.0010) between amplified c-myc gene and inflammatory carcinoma, a particularly aggressive breast cancer. The c-erbB-2 gene was amplified in 22% of the tumor samples and a rearrangement was observed once. Alteration of the c-erbB-2 gene was significantly linked to histological grade III tumors (P = 0.005) and the absence of estrogen and progesterone receptors (P = 0.036). No amplifications were observed for c-erbB-1, c-Ki-ras, and c-Ha-ras genes. About 40% of breast carcinomas contain either amplified c-myc or c-erbB-2 protooncogenes, whereas simultaneous amplification of both was seen in only one sample, suggesting the involvement of two distinct molecular mechanisms in breast cancer. Comparison of DNA from peripheral blood and tumor samples indicated loss of one c-Ha-ras allele in 29% of patients heterozygous for this polymorphism. A significant correlation (P = 0.016) between c-Ha-ras locus (11p14) allele loss and patient survival was found. These data suggest that 11p14 allelic loss plays a role in the evolution of human breast cancer, amplification of c-erbB-2 gene is associated with increasing stage of malignancy, and alteration of the c-myc gene in inflammatory breast carcinoma may contribute to the rapid progression of this human tumor subtype.
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Type II connatal Pelizaeus-Merzbacher disease is a degenerative disease of the developing nervous system. Confirmation of diagnosis is only by histopathological examination at present. The authors describe an infant with several clinical features which are apparently unique to this disease. These features may allow a presumptive clinical diagnosis to be made in other cases, thereby allowing valuable genetic counselling to be given before the death of the affected infant enables confirmation by autopsy.