DNA hypermethylation is associated with 17p allelic loss in neural tumors.

It has long been debated whether the accumulation of allelic losses in tumors involves the selection of cells which have stochastically lost chromosomal regions or whether there is, inherent to the neoplastic state, a process which predisposes to genetic instability. Changes in DNA methylation are commonly seen in human tumors and can alter chromosome structure. We now have examined specific types of primary neural tumors which allow us to determine relationships between abnormal DNA hypermethylation and allelic loss. In primary brain tumors which frequently lose chromosome 17p (30-50%) even in the earliest stages, we now show that 84% (21 of 25) exhibit hypermethylation at locus D17S5, on 17p. However, in primary neuroblastomas, a tumor type which does not lose chromosome 17p, no regional hypermethylation is observed. These data suggest that on chromosome 17p, regional D17S5 hypermethylation constitutes a molecular change which is associated with genetic instability.

Regional DNA hypermethylation at D17S5 precedes 17p structural changes in the progression of renal tumors.

In a preceding paper for brain tumors, we demonstrate a tight association between regional hypermethylation at locus D17S5 of chromosome 17p and allelic loss of this chromosome. Because 17p allelic losses occur at the earliest stages of brain tumors, the exact temporal relationship between this event and the hypermethylation could not be elucidated. In renal cancers, two linked structural changes on chromosome 17p, allelic loss and p53 gene mutations, generally occur late in progression. We now show that D17S5 hypermethylation is tightly coupled to both of these genetic changes in late stage renal tumors. However, the methylation change is the only one of the 17p abnormalities which occurs at a high incidence in early-stage renal cancers (hypermethylation, 50%; 17p allelic loss, 13%; p53 mutations, 0%). Our results firmly suggest that D17S5 regional hypermethylation precedes the appearance of the consistent 17p genetic changes in renal cancers, suggesting that this event either marks, or may even cause, chromatin changes which predispose to genetic instability.

Distinct hypermethylation patterns occur at altered chromosome loci in human lung and colon cancer.

Regional increases in DNA methylation occur in normally unmethylated cytosine-rich areas in neoplastic cells. These changes could potentially alter chromatin structure to inactivate gene transcription or generate DNA instability. We now show that, in human lung and colon cancer DNA, hypermethylation of such a region consistently occurs on chromosome 17p in an area that is frequently reduced to homozygosity in both tumor types. Over the progression stages of colon neoplasia, this methylation change increases in extent and precedes the allelic losses on 17p that are characteristic of colon carcinomas. We also show on chromosome 3p that regional hypermethylation may nonrandomly accompany chromosome changes in human neoplasia. Increased methylation is consistent in small-cell lung carcinoma DNA at two 3p loci that are constantly reduced to homozygosity in this tumor, but it is not seen in colon cancer DNA, in which these loci are infrequently structurally altered.

Abnormal patterns of DNA methylation in human neoplasia: potential consequences for tumor progression.

An imbalance of DNA methylation, involving widespread hypomethylation, regional hypermethylation and increased cellular capacity for methylation, is characteristic of human neoplasia. This imbalance begins in preneoplastic cells and becomes more extensive throughout subsequent stages of tumor progression. In normal cells, a primary function of DNA methylation may be to modulate compartmentalization of DNA to ensure that regional areas of transcriptionally active chromatin replicate earlier than the bulk transcriptionally inactive chromatin. We argue here that the altered methylation patterns observed during tumor progression, especially regional hypermethylation, may mark--or even help to establish--abnormalities of chromatin organization. In turn, these changes in chromatin structure may, through direct transcriptional inactivation of genes, predisposition to mutations, and allelic deletions, mediate the progressive losses of gene expression associated with tumor development.

The MR appearance of hypothalamic hamartoma.

Hypothalamic hamartoma is the most common detectable cerebral lesion causing precocious puberty. Two histologically confirmed cases were studied by computerized tomography (CT) and magnetic resonance (MR) imaging. T2 weighted, sagittal MR images were superior to CT in delineating the tumor from surrounding grey matter. The lesion was isointense to grey matter on T1 weighted images allowing exclusion of other hypothalamic tumors. MR will undoubtedly become the imaging modality of choice in the detection of hypothalamic hamartoma.

Alpha-glucosidase deficiency and basilar artery aneurysm: report of a sibship.

Glycogen deposition in vascular smooth muscle has been demonstrated previously in alpha-glucosidase deficiency but has not been clinically significant. Three sons of healthy, nonconsanguineous parents developed progressive proximal muscular weakness secondary to alpha-glucosidase deficiency. Each patient developed a fusiform basilar artery aneurysm, which was complicated by fatal rupture in two patients and a cerebellar infarction in the third. Postmortem examination demonstrated severe vacuolation of skeletal muscle, liver, and vascular smooth muscle with accumulation of periodic acid-Schiff-positive, diastase-sensitive material. In the surviving brother, similar glycogen deposition was demonstrated in the smooth muscle of the superficial temporal artery. Basilar artery aneurysm formation in this sibship may be a consequence of alpha-glucosidase deficiency.