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Biomedical subjects

C M Steel

Publications and source records attributed to C M Steel.

At least 73 records · Page 4Linked to original sources
PubMed1994

Identification and characterisation of cancer genes.

Cancer genes have been subdivided into oncogenes and tumour suppressors though the distinction is not entirely valid. In many cases their effects can be demonstrated by induction or reversal of a transformed phenotype following transfection into a suitable host cell but full characterisation requires isolation by positional cloning and analysis of function at the molecular level. Almost all have been ascribed some function within the complex pathways of signal generation, receipt and response that regulate cell growth and differentiation. However, few, if any, tumours result from just a single mutation and the key to a real understanding of the molecular basis of malignancy must be studies, currently in their infancy, of interactions between the various genes implicated in the initiation and progression of cancer.

Cloning, Molecular↗
PubMed1993

In utero rearrangements in the trithorax-related oncogene in infant leukaemias.

The majority (approximately 75%) of infant acute leukaemias have a reciprocal translocation between chromosome 11q23 and one of several partner chromosomes. The gene at 11q23 (named MLL, ALL-1, HRX or HTRX-1; refs 2-6) has been cloned and shares homology with the Drosophila developmental gene trithorax. Rearrangements of this gene (called HRX here) occur in introns and cluster in a region of approximately 10 kb; individual patients have different breakpoints. Here we describe three pairs of infant twins with concordant leukaemia who each share unique (clonal) but non-constitutive HRX rearrangements in their leukaemic cells, providing evidence that the leukaemogenic event originates in utero and unequivocal support for the intra-placental 'metastasis' hypothesis for leukaemia concordance in twins.

Chromosomes, Human, Pair 11↗
PubMed1993

Linkage mapping in familial breast cancer: improved localisation of a susceptibility locus on chromosome 17q12-21.

Fifteen pedigrees with a total of 75 cases of breast cancer, 10 of ovarian cancer and 53 of other cancers have been collected. Polymorphic markers on chromosome 17q have been screened to locate a putative breast-cancer gene using DNA from relevant individuals within these families. Pairwise LOD scores have been calculated for markers CMM86, NM23, 42D6 and MFD188. The maximal summated LOD for the 15 families is 4.45 at theta = 0.025 using 42D6. All cases of bilateral breast cancer and ovarian cancer appear to be linked to this region. Recalculating LOD scores on the assumption of linkage in these cases increases the maximal summated LOD to 5.62 at theta = 0.025 using 42D6. A genetic exclusion map of critical recombinants in linked families suggests that the gene is flanked by markers 42D6 and MFD188, a region 5 to 10 cm in length.

Adult↗
PubMed1993

Genetic linkage analysis applied to unaffected women from families with breast cancer can discriminate high- from low-risk individuals.

Up to 20 per cent of cases of breast cancer diagnosed in women under the age of 45 years may be caused by an autosomal dominant gene. A present difficulty is differentiation of mutation carriers from non-mutation carriers in high-risk families. Genetic linkage analysis has been used to localize a susceptibility gene (BRCA1) on chromosome 17q12-21 between markers 42D6 and MFD188, a region 5-10 million base pairs in length. Odds in favour of linkage to this region were greater than 100,000:1 in 15 families with breast cancer. In eight families in which the probability of linkage was above 75 (range 79.2-99.9) per cent, 19 women were identified who were at high lifetime risk of breast cancer (range 80.6-87.2 per cent) and 37 whose risk was similar to that for the general population (range 9.8-16.4 per cent). Genetic risk prediction of this kind may enable high-risk screening clinic resources to be concentrated on those most likely to benefit.

Adult↗
PubMed1993

The frequency of micronuclei in bone-marrow erythroblasts during the treatment of childhood acute lymphoblastic leukaemia.

We scored the frequency of micronuclei in bone-marrow erythroblasts from 41 patients with childhood acute lymphoblastic leukaemia (childhood ALL) at diagnosis and during their 2-year treatment cycle in order to see whether there would be any variation in the cytogenetic damage induced by chemotherapy. We found that most patients showed the same trend in micronucleus frequency, with a progressive rise from the diagnostic slide through induction to pre-intensification and completion of treatment. The rise was attributed to damage to the erythroblasts occurring as a result of chemotherapy, and was judged not prognostically significant in this study.

Adolescent↗
PubMed1993

Cervical carcinoma: low frequency of allele loss at loci implicated in other common malignancies.

Twenty cervical carcinomas were examined for loss of heterozygosity (LOH) using 22 RFLP markers, which mapped to regions of putative oncosuppressor gene loci, identified as candidates in other common solid tumours. Allele losses were identified in six of the eight chromosomal arms examined, but at a significantly lower frequency than that reported in other common solid tumours. No association was observed between allele losses at any chromosomal location and the presence or integration of 'high risk' types of HPV determined by a sensitive, specific PCR method. HPV 16, 18 or 33 were found in the majority (75%) of these tumours. We have looked at only a limited subset of chromosomal regions, but the results, so far, imply that carcinoma of the cervix may arise by different molecular events than other common solid tumours, and support the view that one of the distinctive events may be infection with HPV. Alternatively, similar molecular events may be occurring, but in regions of the genome not yet identified as targets in other solid tumours.

Alleles↗
PubMed1993

Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer.

Thirty-four primary, untreated sporadic breast cancers were examined for loss of heterozygosity (LOH) at tumour suppressor loci involved in colorectal cancer: APC/MCC at 5q21 and DCC at 18q21. LOH was identified in 28% informative patients at 5q21 and 31% at 18q21. LOH at 5q21 and 18q21 was compared with allele loss at 17p13 and concurrent LOH at two or more of the loci was noted in 24% of tumours. Expression of a 12 kb DCC mRNA was demonstrated in 14/34 (42%) of the cancers and in all five tumours with LOH at the DCC locus there was an additional 11 kb DCC mRNA. Abnormalities of three loci involved in colorectal cancer (5q21, 17p13 and 18q21) therefore also occur in sporadic breast cancer. The accumulation of such genetic abnormalities may confer a growth advantage important in the development of breast cancer.

Alleles↗
PubMed1993

pS2 is an independent factor of good prognosis in primary breast cancer.

In breast cancer, oestrogen regulated genes, such as pS2, may be expressed in well differentiated tumours with a good prognosis. We have examined pS2 mRNA expression in 78 primary, untreated breast cancers and related pS2 expression to disease behaviour and known prognostic factors. pS2 mRNA expression was detected in 25/78 (32%) of cancers and was significantly associated with a moderate/high oestrogen receptor content (P = 0.045, Chi Square test). pS2 mRNA expression was associated with freedom from disease at median 31 months clinical and radiological follow-up (P = 0.015, Fisher's exact test, odds ratio 8.6). Using multiple logistic regression analysis of six potential prognostic factors only pathological axillary node status (P < 0.01) and pS2 mRNA expression (P < 0.05) provided independent prognostic information. Furthermore, pS2 was associated with a good prognosis in the axillary node positive patients where only 1/13 (8%) with pS2 mRNA expression compared with 13/29 (45%) without detectable expression had recurrence of their disease. These data provides strong support for pS2 as a useful independent prognostic factor in primary breast cancer.

Adult↗
PubMed1993

Evidence for a new tumour suppressor locus (DBM) in human B-cell neoplasia telomeric to the retinoblastoma gene.

Roughly 25% of human B-cell chronic lymphocytic leukaemias (CLL) are characterized by a chromosomal lesion involving 13q14. This region contains the retinoblastoma gene (RB1). We have used a variety of techniques to determine whether RB1 or some other locus is the critical region in 11 cases of low grade B-cell malignancy (mainly CLL), all with deletions or translocations involving 13q14. In all cases, except the one with minimal disease, there was deletion or a structural lesion in the region of D13S25, with at least 4 cases showing homozygous disruption. We conclude that D13S25 lies close to a tumour suppressor locus whose inactivation contributes to the initiation or progression of low grade B-cell malignancy. This locus is located at least 530 kilobases telomeric to RB1.

Alleles↗
PubMed1993

A comparison of micronucleus frequency and radiation survival in lymphoblastoid cell lines.

The relationship between the formation of micronuclei (MN) following the treatment of cell lines with ionizing radiation and the radiation survival of cell lines is important as the MN assay has the potential to predict radiation survival. Studies investigating the relationship have reached conflicting conclusions. We examined the relationship between MN formation and radiation survival measured by a clonogenic assay in six lymphoblastoid cell lines over a dose range of 0-2.0 Gy. We did not find a predictive relationship between the radiation induced MN frequency and the radiation survival in these cell lines. Possible reasons for the lack of correlation include variations in the percentage of scorable cells after irradiation and culture with cytochalasin B, different numbers of cells in the G1 phase of the cell cycle at the time of irradiation, a greater toleration of the loss of MN by hyperdiploid cell lines compared to diploid cell lines and quantitative differences in the conversion of chromosomal fragments into MN for the cell lines.

Aneuploidy↗
PubMed1993

Linkage of a major breast cancer gene to chromosome 17q12-21: results from 15 Edinburgh families.

DNA from members of 15 pedigrees each containing between three and eight cases of breast cancer have been collected from southeastern Scotland. Polymorphic markers on chromosome 17q were screened to locate a putative breast cancer gene by using DNA from relevant individuals within these families. Pairwise LOD scores were calculated for markers D17S74, NM23, D17S588, and D17S579. The maximal summated LOD for the 15 families was 5.44 at theta = .034, when D17S588 (42D6) was used. In these breast cancer families, a subset which did not give evidence for linkage to this region could be identified.

Adult↗
PubMed1992

p53 mutations in breast cancer.

We have identified and analyzed 41 mutations in p53 in sporadic breast tumors from 136 unselected breast cancer patients and estimate that approximately 40% of such tumors contain p53 mutations. The frequency of G-T transversions and the incidence of guanosine mutations in the nontranscribed strand of the p53 gene were found to be higher than expected, and we suggest, therefore, that exogenous carcinogens have an etiological role in sporadic breast cancers. Mutations were recorded in 44 codons of the p53 gene, with no obvious mutational hot-spots, although mutations at codons 175, 194, 273, and 280 accounted for 25% of the changes. One germ-line mutation was found in 136 patients and so we conclude that constitutional mutation of p53 may be an uncommon etiological factor in breast cancer.

Base Composition↗
PubMed1992

Insertion of SMRV-H viral DNA at the c-myc gene locus of a BL cell line and presence in established cell lines.

Mutation of the c-myc gene locus has occurred during in vitro culture of the Burkitt lymphoma cell line Namalwa. Gene cloning and sequencing of this c-myc gene locus has revealed the insertion of incomplete copies of the Squirrel Monkey Retrovirus-Human (SMRV-H) proviral genome. Insertions of the SMRV-H genome were seen in all Namalwa cell lines tested, with multiple insertions being seen in some sublines. Viral particles with the morphology of type-D retrovirus, budding from these cells, were seen by transmission EM. New insertions of the genome were produced spontaneously in these cells. The origins of the type-D retrovirus and its implications for workers in the field are discussed.

Base Sequence↗