Miguel Bronchud: Osteosarcoma as a remarkable example of a cancer characterized by chromothripsis

Miguel Bronchud, Co-Founder and Advisory Board at Regenerative Medicine Solutions, shared on LinkedIn:

“Osteosarcoma is the most common primary cancer of bone with a peak incidence in children and young adults. Clinical outcomes and overall survival have hardly improved over the past four decades, with combinations of surgery (often limb amputation) and platinum based chemotherapy. Lung metastatic disease is frequent in aggressive osteosarcomas and usually lethal. Despite progress, the genomic aberrations underpinning osteosarcoma evolution remain poorly understood.

Like many blood cancers (or hematological malignant disease), human sarcomas rely for their growth and development on fragmentation of chromosomes and frequently the consequent generation of ‘fusion proteins’ – as a result of chromosomal translocations , with one bit of a chromosome joining another abnormal chromosome.

Unlike most commoner human epithelial cancers (like breast, prostate,lung, colorectal, bladder, kidney etc), the fusion proteins that result from some chromosomes translocations can be targeted by anti oncogene small drugs, like the almost magic Gleevec (Imatinib) in chronic myeloid leukemia (CML).

Whole-genome sequencing (WGS) studies of tumors have recently revealed that most human cancers are riddled by complex forms of structural variation.

A major mutational process driving cancer genome complexity is ‘chromothripsis’, which refers to the acquisition of tens to hundreds of clustered rearrangements in one or a few chromosomes resulting from chromosomal shattering in micronuclei or through fragmentation of dicentric chromosomes during anaphase bridge resolution.

Chromothripsis is pervasive across diverse cancer types, and it often mediates malignant transformation and drug resistance. A remarkable example of a cancer characterized by chromothripsis is osteosarcoma but no magic inhibitors of key fusion cancer drivers proteins are yet available

Paper- ‘Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution’- recently published before peer review by the European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SA, UK

Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution: Cell

Authors: Jose Espejo Valle-Inclan, Solange De Noon, Katherine Trevers, Hillary Elrick, Ianthe A.E.M. van Belzen, Sonia Zumalave, Carolin M. Sauer, Mélanie Tanguy, Thomas Butters, Francesc Muyas, Alistair G. Rust, Fernanda Amary, Roberto Tirabosco, Adam Giess, Alona Sosinsky, Greg Elgar, Adrienne M. Flanagan, Isidro Cortés-Ciriano

Chromosome 17p shows the shortest telomere length relative to other human chromosomes, and these researchers hypothesized that the initial double-strand break within or downstream of TP53, which triggers LTA chromothripsis, could result from the resolution of a dicentric chromosome caused by the fusion of two sister chromatids of chromosome 17p in the context of telomere crisis.;

their results suggest that resolution of a dicentric chromosome arising from end-to-end chromosome fusion of the wild-type copy of chromosome 17 with its sister chromatid might not be the only trigger of LTA chromothripsis. Interestingly, highest rates of LTA chromothripsis involving TP53 were observed in uterine carcinosarcoma (UCS, 4%, 2/50), bladder urothelial carcinoma (BLCA, 2.9%, 11/376), and soft-tissue sarcomas (SARCs, 2.3%, 5/219)”