Mutational game changer: Chromothripsis and its emerging relevance to cancer

Luijten, Monique N.H.; Lee, Jeannie Xue Ting; Crasta, Karen

doi:10.1016/j.mrrev.2018.06.004

Cited by 58 publications

(52 citation statements)

References 168 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A major copy number of 2 or more was exhibited by 66.44% and 53.73% of the autosomal genome for R1 and M, respectively. The copy-number profile of sample R2 was distinct from other tumors in the presence of oscillations in chromosome segment copy number, similar to chromothripsis events (Luijten et al 2018) or extrachromosomal DNA amplifications (deCarvalho et al 2018).…”

Section: Genomic Analysesmentioning

confidence: 90%

Molecular and clonal evolution in recurrent metastatic gliosarcoma

Anderson

Tan

Parkinson

et al. 2020

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence was observed in the brain and bone, and biopsy confirmed metastases in the pelvic bones. To understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole-genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared their mutational and copy-number profiles and inferred the clonal phylogeny. The tumors harbored shared alterations in GBM driver genes, including mutations in TP53, NF1, and RB1, and CDKN2A deletion. Whole-genome doubling was identified in the first recurrence and the extracranial metastasis. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.

show abstract

Section: Genomic Analysesmentioning

confidence: 90%

Molecular and clonal evolution in recurrent metastatic gliosarcoma

Anderson

Tan

Parkinson

et al. 2020

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

show abstract

“…As above, the more pronounced phenotypes typically occurring in HCT116 likely reflects their distinct genetic status, particularly since they harbor a MLH1 deficiency rendering them DNA mis-match repair defective [9]. Remarkably, although chromosome breakages ( Figure 3E) occurred for each gene, silencing of DSN1, NUF2 and SKP1 induced extensive chromosomal breakages or "shattering" (Figure 3F,G) that are indicative of replication stress and chromothripsis, a catastrophic chromosome fragmentation event resulting in complex chromosome rearrangements that induce tumorigenesis [24,25]. Collectively, these show that reduced gene expression corresponds with increases in numerical and structural defects, further confirming their status as novel CIN genes.…”

Section: Reduced Gene Expression Drives Increases In Chromosome Aberrmentioning

confidence: 99%

Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover

Thompson

Baergen

Lichtensztejn

et al. 2020

Cancers

View full text Add to dashboard Cite

Chromosome instability (CIN), or progressive changes in chromosome numbers, is an enabling feature of many cancers; however, the mechanisms giving rise to CIN remain poorly understood. To expand our mechanistic understanding of the molecular determinants of CIN in humans, we employed a cross-species approach to identify 164 human candidates to screen. Using quantitative imaging microscopy (QuantIM), we show that silencing 148 genes resulted in significant changes in CIN-associated phenotypes in two distinct cellular contexts. Ten genes were prioritized for validation based on cancer patient datasets revealing frequent gene copy number losses and associations with worse patient outcomes. QuantIM determined silencing of each gene-induced CIN, identifying novel roles for each as chromosome stability genes. SKP1 was selected for in-depth analyses as it forms part of SCF (SKP1, CUL1, FBox) complex, an E3 ubiquitin ligase that targets proteins for proteolytic degradation. Remarkably, SKP1 silencing induced increases in replication stress, DNA double strand breaks and chromothriptic events that were ascribed to aberrant increases in Cyclin E1 levels arising from reduced SKP1 expression. Collectively, these data reveal a high degree of evolutionary conservation between human and budding yeast CIN genes and further identify aberrant mechanisms associated with increases in chromothriptic events.

show abstract

“…DNA released from micronuclei triggers cGAS accumulation and activation of proinflammatory response (Harding et al 2017;Mackenzie et al 2017). Following chromothripsis, fragmented chromosomes can assemble randomly, resulting in chromosome rearrangements (Luijten et al 2018). Chromatid breaks, radial chromosomes, anaphase DNA bridges, lagging chromosomes, and micronuclei are all common in BRCA1/2-deficient cells treated with PARP inhibitors (Fig.…”

Section: Amplifying Genomic Instability With Parp and Parg Inhibitorsmentioning

confidence: 99%

PARP and PARG inhibitors in cancer treatment

2020

View full text Add to dashboard Cite

Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.

show abstract

Mutational game changer: Chromothripsis and its emerging relevance to cancer

Cited by 58 publications

References 168 publications

Molecular and clonal evolution in recurrent metastatic gliosarcoma

Molecular and clonal evolution in recurrent metastatic gliosarcoma

Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover

PARP and PARG inhibitors in cancer treatment

Contact Info

Product

Resources

About