Evidence for a pre-malignant cell line in a skin biopsy from a patient with Nijmegen breakage syndrome

Abstract

BackgroundNijmegen breakage syndrome is an autosomal recessive disorder characterized by microcephaly, immunodeficiency, hypersensitivity to X-irradiation, and a high predisposition to cancer. Nibrin, the product of the NBN gene, is part of the MRE11/RAD50 (MRN) complex that is involved in the repair of DNA double strand breaks (DSBs), and plays a critical role in the processing of DSBs in immune gene rearrangements, telomere maintenance, and meiotic recombination. NBS skin fibroblasts grow slowly in culture and enter early into senescence.Case presentationHere we present an incidental finding. Skin fibroblasts, derived from a 9 year old NBS patient, showed a mosaic of normal diploid cells (46,XY) and those with a complex, unbalanced translocation. The aberrant karyotype was analysed by G-banding, comparative genomic hybridization, and whole chromosome painting. The exact breakpoints of the derivative chromosome were mapped by whole genome sequencing: 45,XY,der(6)(6pter → 6q11.1::13q11 → 13q21.33::20q11.22 → 20qter),-13. The deleted region of chromosomes 6 harbors almost 1.400 and that of chromosome 13 more than 500 genes, the duplicated region of chromosome 20 contains about 700 genes. Such unbalanced translocations are regularly incompatible with cellular survival, except in malignant cells. The aberrant cells, however, showed a high proliferation potential and could even be clonally expanded. Telomere length was significantly reduced, hTERT was not expressed. The cells underwent about 50 population doublings until they entered into senescence. The chromosomal preparation performed shortly before senescence showed telomere fusions, premature centromere divisions, endoreduplications and tetraploid cells, isochromatid breaks and a variety of marker chromosomes. Inspection of the site of skin biopsy 18 years later, presented no evidence for abnormal growth.ConclusionsThe aberrant cells had a significant selective advantage in vitro. It is therefore tempting to speculate that this highly unbalanced translocation could be a primary driver of cancer cell growth.Electronic supplementary materialThe online version of this article (10.1186/s13039-018-0364-6) contains supplementary material, which is available to authorized users.

Telomere attrition and dysfunction: a potential trigger of the progeroid phenotype in nijmegen breakage syndrome

“…We therefore hypothesized that NBS is a telomeropathy [ 21 , 22 ], and that telomere abnormalities may accelerate cancer manifestation. Shorter telomeres have been described in individual NBS cases, for both NBS lymphocytes [ 23 , 24 ] and fibroblasts [ 25 ]. Nonetheless, a systematic investigation has not yet been carried out, and the importance of MRN in general and nibrin in particular for telomere length and function are unclear.…”