Imprinting of IGF2 and H19: lack of reciprocity in sporadic Beckwith-Wiedemann syndrome.

Genomic imprinting is a novel form of control of gene expression in which the transcription of each allele of an imprinted gene is dependent on the sex of the gamete from which it was derived; to date > 15 genes have been demonstrated to show imprinting. The maintenance of a normal imprinting pattern in many loci has been shown to be essential for normal development and adult life. Many tumours, and some developmental disorders, exhibit loss of imprinting (LOI) in key genes such as insulin-like growth factor 2 (IGF2) which often results in hyperplasia and is associated with cancer.

Imprinting in clusters: lessons from Beckwith-Wiedemann syndrome.

Imprinted genes in mammals can be clustered in the genome. This raises important questions about mechanistic and functional relationships between imprinted genes in a cluster. The insulin-like growth factor II (IGF2) gene is paternally expressed and is surrounded by maternally expressed genes.

Analysis of multiple renal cell adenomas and carcinomas suggests allelic loss at 3p21 to be a prerequisite for malignant development.

Multiple renal cell tumours from three unrelated patients have been analysed for loss of heterozygosity of 3p, mutation of VHL, and chromosome 7 and 17 imbalances. Loss of 3p alleles is characteristic for clear cell type tumours and the combination of +7, +17 for chromophilic cell type tumours. Thus, we could classify adenomas and carcinomas of the three patients according to the genomic patterns of the tumours.

Frequency of BCL-2/J(H) translocations in peripheral blood of follicular lymphoma patients.

Polymerase chain reaction (PCR) assays have been developed for follicular lymphoma-associated BCL-2/J(H) translocations. Few data are available on the quantitation by PCR of these translocations in peripheral blood mononuclear cells (PBM) of follicular lymphoma (FL) patients. We report that only one of five studied FL patients had a high level of these translocations in the circulation, namely, about 35,000 translocations per 5 x 10(6) PBM.

Focal dermal hypoplasia (Goltz syndrome) presenting as a severe fetal malformation syndrome.

A fetal malformation syndrome comprising growth retardation, anophthalmia, bilateral diaphragmatic herniae, bifid lower leg, syndactyly of the fingers, malrotation of the colon, hypoplastic kidneys and total anomalous pulmonary venous drainage is described in a female fetus from a consanguineous relationship. Differential diagnosis is discussed and it is suggested that this case represents an unusually severe form of Goltz syndrome.

Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL.

Inherited predisposition to phaeochromocytoma (MIM No 171300) occurs in multiple endocrine neoplasia type 2 (MEN 2) (MIM No 171400), von Hippel-Lindau (VHL) disease (MIM No 199300), and neurofibromatosis type 1 (NF1) (MIM No 162200). In addition, familial phaeochromocytoma alone has also been reported and we and others have identified germline VHL mutations in five of six kindreds analysed previously. Germline mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, and in the VHL tumour suppressor gene cause MEN 2 and VHL disease, respectively.

Treatment of Kaposi's sarcoma after solid organ transplantation.

Purpose: This retrospective review of all patients who developed Kaposi's sarcoma (KS) after solid organ transplantation at a single institution was undertaken to define the clinical presentation of this malignancy in the setting of iatrogenic immunodeficiency, and to determine the most appropriate treatment for patients in this clinical setting.

Materials And Methods: The records of 2,099 patients who underwent heart, lung, liver, or kidney transplantation at The Toronto Hospital between January 1, 1981 and June 30, 1995, were reviewed. Twelve patients were identified who developed biopsy-proven KS in the posttransplantation period.

Ethical and intellectual property in the biological sciences.

Ethical concerns on patents in the biological sciences are increased by the prospect of patents for higher life forms. A Canadian patent grants the owner the right to exclude others in Canada from making, using, or selling or offering for sale his or her invention for the term of the patent; however, it does not give the patent owner any positive rights to do likewise. As with other forms of property, the right to make, use, or sell a patented invention may be regulated by other laws or guidelines.

Epigenetic modification and uniparental inheritance of H19 in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome associated with a characteristic pattern of visceromegaly and predisposition to childhood tumours. BWS is a genetically heterogeneous disorder; most cases are sporadic but approximately 15% are familial and a small number of BWS patients have cytogenetic abnormalities involving chromosome 11p15. Genomic imprinting effects have been implicated in familial and non-familial BWS.

A molecular, clinical, and immunohistochemical study of vestibular schwannoma.

The molecular pathogenesis of vestibular schwannoma has been investigated by determining the extent of chromosome 22 loss of heterozygosity in 77 tumors and relating these findings to clinical and immunohistochemical indexes of tumor behavior. Loss of heterozygosity was looked for at eight chromosome 22q loci. Clinical details were obtained in all 77 cases, and a clinical growth index was calculated for each tumor.

Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.

Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder predisposing to retinal and CNS hemangioblastomas, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. Interfamilial differences in predisposition to pheochromocytoma reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma. We investigated the mechanism of tumorigenesis in VHL disease tumors to determine whether there were differences between tumor types or classes of germ-line mutations.

Pheochromocytoma in dogs and cats.

Pheochromocytomas are endocrine tumors arising from chromaffin cells (pheochromocytes) of the adrenal glands in dogs and cats. The clinical symptomatology produced results from the direct presence and space-occupying nature of the tumor, or the secondary presence of excessive amounts of excreted catecholamines. Diagnosis and management of pheochromocytomas remain great challenges for veterinary clinicians.

Mutation analysis of glial cell line-derived neurotrophic factor (GDNF), a ligand for the RET/GDNF receptor alpha complex, in sporadic phaeochromocytomas.

Phaeochromocytomas usually occur sporadically but may also be a feature of three autosomal dominantly inherited cancer syndromes, multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and, very rarely, type 1 neurofibromatosis. Germ-line missense mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2. In VHL, germ-line mutations in one of the three exons of the VHL tumor suppressor gene have been found in the majority of families.

Development and clinical application of an innovative fluorescence in situ hybridization technique which detects submicroscopic rearrangements involving telomeres.

We report an innovative fluorescence in situ hybridization technique which exploits a unique resource of 41 telomere-specific probes and allows the simultaneous analysis of the subtelomeric region of every chromosome for deletion, triplication and balanced translocation events. This technique requires only a single microscope slide per patient and is expected to be a useful diagnostic tool with applications in the fields of idiopathic mental retardation, the detection of congenital abnormalities and in some forms of cancer. This will lead to more accurate genetic counselling of patients and their families and will provide the basis for future diagnostic, therapeutic and preventative measures.

Microsatellite instability in early onset and familial colorectal cancer.

Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci.

Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway.

The Beckwith-Wiedemann syndrome (BWS) is genetically linked to chromosome 11p15.5, and a variety of observations suggest that deregulation of imprinted genes in this region is causally involved in the pathogenesis of the disease. It has been shown that in some patients without cytogenetic abnormalities the otherwise repressed maternal copy of the insulin-like growth factor 2 (IGF2) gene is expressed, leading to biallelic expression of IGF2.

Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation.

Desmoid tumours are generally very rare but occur about 100 times more frequently in the colorectal cancer predisposition syndrome familial adenomatous polyposis (MIM 175100), being represented in about 10% of patients. In addition to desmoid disease occurring in familial adenomatous polyposis (FAP) there exist familial infiltrative fibromatosis (MIM 135290) kindreds where there is no evidence of FAP. Previously we have described a kindred with familial infiltrative fibromatosis (FIF) in which desmoid tumours were associated with nonpolyposis colorectal cancer.

Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome.

Germline mutations in four human mismatch repair genes (MSH2, MLH1, PMS1, and PMS2) have been reported to cause hereditary non-polyposis colon cancer syndrome (HNPCC). The identification of germline mutations in HNPCC kindreds allows precise diagnosis and accurate predictive testing. To investigate further the genetic epidemiology of HNPCC and the nature and frequency of germline mutations in this disorder, we studied 17 English HNPCC kindreds for germline mutations in MSH2 and MLH1.

Pericardial sclerosis as the primary management of malignant pericardial effusion and cardiac tamponade.

Objectives: The management of malignant pericardial effusion remains controversial. We present our experience with 93 patients referred for drainage and sclerosing procedures between 1979 and 1994.

Methods: With continuous electrocardiographic monitoring, a Kifa catheter was inserted percutaneously into the pericardial sac and allowed to drain.

A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map.

Karyotypic analysis in a patient with Peutz-Jeghers' syndrome demonstrated a pericentric inversion on chromosome 6. Further investigation was undertaken using fluorescence in situ hybridisation (FISH) with yeast artificial chromosome clones selected to contain genetic markers from chromosome 6, and a probe for the centromeric alphoid repeat array. This analysis located one inversion breakpoint within the alphoid array, in a 1-cM interval between D6S257 and D6S402, and the other in a 4-cM interval between D6S403 and D6S311.

Fertility, reproductive outcomes, and health of offspring, of patients treated for Hodgkin's disease: an investigation including chromosome examinations.

Reproductive outcomes and health of offspring were investigated in 340 patients with Hodgkin's disease first treated at Mount Vernon Hospital, Middlesex, England, at ages under 40 (females) or 45 (males) during 1970-91. Information on offspring was obtained from case-notes and postal questionnaires to the patients. Eleven men and 16 women who had conceived any children after treatment were then interviewed.

Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis.

The von Hippel-Lindau (VHL) disease product is thought to down-regulate transcription by antagonizing elongin-enhanced transcriptional elongation. Germline VHL gene mutations predispose to the development of retinal, cerebellar and spinal haemangioblastomas, renal cell carcinoma and phaeochromocytoma. In addition, somatic Inactivation of the VHL gene is frequent in sporadic renal cell carcinoma and haemangioblastoma.