Clonality of tuberous sclerosis harmatomas shown by non-random X-chromosome inactivation

Abstract

Tuberous sclerosis (TSC) is an autosomal dominant condition characterised by tumour-like malformations (hamartomas) in the brain and other organs. A proportion of hamartomas from patients with TSC show loss of heterozygosity (LOH) for DNA markers in the region of either the TSC1 gene on chromosome 9q34 or the TSC2 gene on 16p13.3. This implies that these lesions are clonal. We have studied X-chromosome inactivation, as a marker of clonality, in 13 hamartomas from females with TSC. The hamartomas comprised five renal angiomyolipomas, three fibromas and seven other lesions. In previous studies, four of the lesions showed LOH. A polymerase chain reaction assay was used to analyse differential methylation of an HpaII restriction site adjacent to the androgen-receptor triplet-repeat polymorphism on Xq11-12. In 12 of the lesions, there was a skewed inactivation pattern with one X chromosome being fully methylated and the other unmethylated. Normal tissue showed a random pattern of inactivation. These data confirm that most TSC hamartomas are clonal in origin. This is an intriguing finding, since these lesions are composed of more than one cell type.

Low Grade Glandular Lesions of the Sinonasal Tract: A Focused Review

“…Ozolek et al on the other hand described loss of heterozygosity rates (fractional allelic losses) for REAH that are intermediate between inflamed mucosa and sinonasal adenocarcinoma and suggested that it may represent a benign neoplasm [9]. This would be in keeping with the finding of a neoplastic origin for many other so-called hamartomas in the body, such as angiomyolipoma of the kidney [10]. Jo et al [11] have suggested that REAH and the related seromucinous hamartomas (see below), may be more accurately designated as ''adenomas'', reflecting this possible neoplastic nature.…”

Multiple Angiomyolipomata of the Liver: A Case Report

“…AMLs have been regarded as hamartomas; however, clonality assays performed in a recent study of renal AMLs has shown the myoid and the vascular components to be monoclonal, implying a neoplastic proliferation (15,16). The adipose tissue component of the AML was found to be polyclonal and the authors speculate that the fat is metaplastic or a reactive change in the neoplasm.…”

Lymphangioleiomyomatosis andTSC2-/-Cells

“…Attempts to demonstrate a second-hit mutation in TSC skin tumors were mostly negative, and loss of heterozygosity (LOH) at the TSC1 or TSC2 locus was observed in only a few TSC skin tumors. 47,58,[73][74][75] Inability to detect LOH in most samples was likely due to the cellular heterogeneity of these tumors. This problem was surmounted by using fluorescence in situ hybridization to analyze individual nuclei, which documented allelic deletion for TSC2 in dermal touch preparations of 8=8 angiofibromas and 6=7 periungual fibromas.…”