Peter J. Smith

Loss of alleles on the short arm of chromosome 11 in a hepatoblastoma from a child with Beckwith-Wiedemann syndrome

SummaryThe Beckwith-Wiedemann syndrome (BWS) is characterised by multiple congenital abnormalities, including exomphalos, macroglossia, and gigantism. It is also associated with an elevated risk of embryonal neoplasia and occasionally with constitutional anomalies of chromosome band 11p15. A common pathogenetic mechanism for the development of several embryonal tumours has been proposed involving the loss of somatic heterozygosity for a locus on the short arm of chromosome 11. In support of this hypothesis, we have recently reported generation of homozygosity for the c-Ha-ras-1 protooncogene in an adrenal adenoma from an adult BWS patient. In this study wer report the generation of homozygosity for a region on the short arm of chromosome 11 defined by the calcitonin (11p13-15) and insulin (11p15-15.1) genes in a hepatoblastoma from a child with BWS.

Molecular changes associated with induction of cell death in a human T-cell leukaemia line: Putative nucleases identified as histones

Following treatment of the human T-cell leukaemia line, CEM-C7, with the glucocorticoid, dexamethasone, a rapid decrease in viability occurred after 40 h which coincided with fragmentation of DNA in these cells. A similar pattern of DNA fragmentation was observed when these cells were gamma-irradiated or treated with cycloheximide. Distinct morphological changes occurred after treatment, indicating a form of cell death, regulated from within, termed apoptosis. A set of nuclear proteins ranging in size from 10-18 kDa appeared by 40 h following treatment with dexamethasone. Treatment of cells with gamma-irradiation or cycloheximide also produced the same protein pattern. This set of proteins, and a doublet approximately 55 kDa in size, had apparent nuclease activity which was not observed in untreated cells. However, protein microsequencing of these bands in the 10-18 kDa region revealed that they were histone proteins. These results cast doubt on a recent report which provided evidence that these proteins were induced nucleases.

Generation of homozygosity at the c-Ha-ras-1 locus on chromosome 11p in an adrenal adenoma from an adult with Wiedemann-Beckwith syndrome

Generation of homozygosity for the human c-Ha-ras-1 locus on the short arm of chromosome #11 (11p) has been demonstrated for an adrenal adenoma from an adult with Wiedemann-Beckwith syndrome (WBS). This is the first demonstration of loss of somatic heterozygosity for a locus on 11p in an adrenal neoplasm and is the first instance where a tumor of any type, from a patient with WBS, shows loss of heterozygosity in this region of the genome. Generation of homozygosity in an adenoma, rather than a carcinoma, demonstrates that this mechanism is an early event in tumorigenesis rather than a late event associated with tumor progression.

MYCL genotypes and loss of heterozygosity in non-small-cell lung cancer

Some studies have suggested that the S allele of the MYCL oncogene, which results from an intragenic EcoRI restriction fragment length polymorphism (RFLP), may be associated with cancer susceptibility. In addition, this allele has also been linked to metastases and adverse survival in certain cancers, although studies of lung cancer patients from different populations have yielded controversial results. We studied 108 cases of surgical resected non-small-cell lung cancer (NSCLC) and found no evidence that MYCL genotypes were associated with tumour progression or a worse prognosis. However, the presence of loss of heterozygosity (LOH) at this chromosome 1p32 locus correlated significantly with regional lymph node involvement, as well as advanced TNM stage. These data indicate the existence of a chromosome 1p candidate tumour-suppressor gene(s), possibly in linkage disequilibrium with the EcoRI RFLP in specific populations, which appears to play a role in determining tumour progression in NSCLC. Refined mapping of the critical region of loss should help attempts to identify and clone the candidate gene.

c-Ha-ras-1 alleles in bladder cancer, Wilms' tumour and malignant melanoma.

SummaryPolymorphism of the human c-Ha-ras-1 gene has been analysed in DNA from 168 individuals using the enzymes MspI and HpaII. In all, 35 bladder cancer patients, 28 melanoma patients, 22 Wilms tumour patients, 24 first-degree relatives of Wilms tumour or melanoma patients and 59 unaffected controls were studied. A total of 13 different fragment sizes was detected, 4 “common” and 9 “unusual”. Of the latter, 4 were observed only in cancer patients or their first-degree relatives. The frequency of unusual alleles was significantly greater in bladder cancer patients and in the combined tumour group than in controls, thus providing support for the association of unique Ha-ras alleles and cancer. Some unaffected relatives of patients carried unusual alleles, and thus there is no absolute relationship between Ha-ras genotype and disease.

Why do some cancer patients receiving chemotherapy choose to take complementary and alternative medicines and what are the risks

Complementary and alternative medicine (CAM) cover a broad and diverse group of treatments and products that do not tend to be widely used by conventional healthcare professions. CAM that is systemically absorbed is the most likely to interfere with concurrent chemotherapy and potentially cause harm to cancer patients. Patients receiving chemotherapy may be consuming CAM to treat cancer, to lessen chemotherapy side effects, for symptom management, or to treat conditions unrelated to their cancer. A small proportion of cancer patients decide to use CAM alone to treat cancer and delay conventional treatment. Cancer patients may be influenced in their CAM decision‐making by others: practitioners, family, friends, spouse and even casual acquaintances met in waiting rooms and support groups. This influence may range from encouraging and supporting the patients decision through to making the decisions for the patient. When tested in rigorous clinical trials, no CAM cancer treatments alone have shown benefit beyond placebo. With the exception of ginger to treat chemotherapy‐induced nausea, there is no compelling evidence overriding risk to take complementary medicines for supportive care during chemotherapy treatment. There is, however, established evidence to use mind–body complementary therapies for supportive care during chemotherapy treatment.

Histopathological and tissue culture studies of a melanizing cell line derived from a retinoblastoma

Summary Histological examination of the enucleated eye of a 7‐mth‐old child revealed a retinoblastoma with areas of rosette formation as well as focal areas of melanin pigmentation. Biopsy derived cells readily established a continuous cell line in liquid culture. The cells which have now been cultured continuously for over 3 yr, were shown to be malignant by being non‐contact inhibitable, by readily forming colonies in semi‐solid nutrient agar medium and by producing tumours in nude mice. When grown to the point of overcrowding in liquid culture the cells became heavily melanized. Electron microscopy of the melanized cultured cells showed the melanin to be contained in melanosomes. These findings suggest that retinoblastomas may be derived from bipotential primitive retinal cells which retain the capacity for both nuclear cell and pigment cell differentiation. Alternatively, separate malignant transformations may have occurred in each of 2 different progenitor cell types committed to a separate differentiation pathway. The clinical behaviour of this tumour has not differed from that expected of non‐pigmented retinoblastomas.

Allelic loss on chromosome 11p is a less frequent event in bilateral than in unilateral Wilms' tumours

Analyses to detect loss of heterozygosity (LOH) were performed at 11 polymorphic loci on chromosome 11 and, using a polymorphic CA repeat sequence in the WT1 gene, on a series of 39 tumours from 28 unilateral and 10 tumours from 6 bilateral Wilms tumour (WT) patients. LOH was seen in 13 out of 35 patients including 12 out of 29 unilateral tumours, but only one of 10 bilateral tumours. This suggests that bilateral WT represents a subgroup of WT in which tumour initiating events less frequently involve LOH on chromosome 11 and that either epigenetic events, point mutations or another non-chromosome 11p locus are important in bilateral tumours. The observation of LOH in one WT but not another WT in a bilateral WT patient provides evidence that these tumours arising in the same patient are not monoclonal proliferations and most likely arise via different molecular pathways.

Adriamycin and cytosine arabinoside contribute equally to prediction of response in acute myelocytic leukemia with improved confidence level

SummarySamples from 15 patients with acute myeloid leukemia (AML) were studied in a colony-inhibition assay of drug sensitivity. In vitro sensitivity to both Adriamycin (Adr) (1-h incubation) and cytosine arabinoside (AraC) (24-h and continuous incubation) were determined, as were the tritiated thymidine suicide indices (SI) during the 24-h incubation with AraC. The sensitivity of the proportion of cells entering S-phase during the 24-h incubation was also evaluated. Using discriminant analysis a function was derived to separate the patients into two groups, those who failed remission induction therapy, or nonresponders (group 1), and those who entered complete remission (group 2). The only variables that contributed to prediction were the Adr (1 h) and Ara-C (24 h) results. Overall, 87% (13/15) of the patients were correctly grouped using this function, with a confidence level for nine of these 13 patients of >80%. Adr and AraC results contributed equally to the prediction.

Lung pathology: the molecular genetics of non-small cell lung cancer

&NA; In Australia, lung cancer is the most common malignancy in males and the largest cause of cancer deaths. Conventional management has not had a dramatic impact on the mortality rates from lung cancer, which has a case‐fatality rate of over 90%. Recent developments in molecular and cellular biology have however, contributed to our knowledge of lung tumorigenesis, which will hopefully translate into clinical benefit for our patients. Many molecular abnormalities are common to both non‐small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) but there are differences between these histological types and even within the NSCLC subtypes. This review concentrates on NSCLC, which accounts for up to 85% of Australian lung cancers.