Human rDNA copy number is unstable in metastatic breast cancers

Abstract

Chromatin-mediated silencing, including the formation of heterochromatin, silent chromosome territories, and repressed gene promoters, acts to stabilize patterns of gene regulation and the physical structure of the genome. Reduction of chromatin-mediated silencing can result in genome rearrangements, particularly at intrinsically unstable regions of the genome such as transposons, satellite repeats, and repetitive gene clusters including the rRNA gene clusters (rDNA). It is thus expected that mutational or environmental conditions that compromise heterochromatin function might cause genome instability, and diseases associated with decreased epigenetic stability might exhibit genome changes as part of their etiology. We find support of this hypothesis in invasive ductal breast carcinoma, in which reduced epigenetic silencing has been previously described, by using a facile method to quantify rDNA copy number in biopsied breast tumors and pair-matched healthy tissue. We found that rDNA and satellite DNA sequences had significant copy number variation-both losses and gains of copies-compared to healthy tissue, arguing that these genome rearrangements are common in developing breast cancer. Thus, any proposed etiology onset or progression of breast cancer should consider alterations to the epigenome, but must also accommodate concomitant changes to genome sequence at heterochromatic loci. Authors' Statement One of the common hallmarks of cancer is genome instability, including hypermutation and changes to chromosome structure. Using tumor tissues obtained from women with invasive ductal carcinoma, we find that a sensitive area of the genome-the ribosomal DNA gene repeat cluster-shows hypervariability in copy number. The patterns we observe as not consistent with an adaptive loss leading to increased tumor growth, but rather we conclude that copy number variation at repeat DNA is a general consequence of reduced heterochromatin function in cancer progression.

Thousands of high-quality sequencing samples fail to show meaningful correlation between 5S and 45S ribosomal DNA arrays in humans

“…Changes in rDNA copy number have been identified in some cancer and aging studies. The 45S and 5S copy numbers change in some human cancers, in which cancerous tissue has a higher or lower rDNA copy number than a matched control [4][5][6][7][8] . In some tissues such as the brain, heart, and adipose tissue, 45S rDNA copy loss has been observed with age [9][10][11] .…”

Recent advances in the nucleolar responses to DNA double-strand breaks

“…Patients with Bloom Syndrome and Ataxia telangiectasia, caused by mutations in the repair proteins BLM and Ataxia telangiectasia mutated (ATM) respectively, have strong predisposition to cancer and rDNA instability ( 58 ). Furthermore, many cancers exhibit pronounced rDNA array instability, often with a reduced rDNA copy-number compared to normal tissue ( 59–62 ). However, the extent to which rDNA instability is a driver of cancer development is still unclear.…”

rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

“…Dysregulated rDNA transcription is linked to a diverse range of human disorders including cancer ( Hannan K.M. et al, 2013 ; Valori et al, 2020 ). This link is underscored by the modulation of rDNA transcription and rDNA silencing during differentiation and tumorigenesis ( Conconi et al, 1989 ; Sanij et al, 2008 ; Grummt and Langst, 2013 ; Hamperl et al, 2013 ; Hayashi et al, 2014 ; Savic et al, 2014 ; Woolnough et al, 2016 ; Diesch et al, 2019 ; Prakash et al, 2019 ).…”

“…These results suggest that rDNA instability may mediate the predisposition for cancer progression. It has been proposed that reduction of rDNA silencing and rDNA instability underpin global genomic instability, and that this can drive the etiology and progression of cancer ( Diesch et al, 2014 ; Wang and Lemos, 2017 ; Xu B. et al, 2017 ; Udugama et al, 2018 ; Valori et al, 2019 ). Nevertheless, it appears that increased rRNA production can be achieved even if the rDNA copy number is reduced ( Wang and Lemos, 2017 ), which can occur by regulating the rate of Pol I transcription per rDNA repeat and/or the number of active rDNA repeats.…”