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Dissecting the impact of genetic variation on mechanisms of cancer

Recent advances in massively parallel DNA sequencing enable identifying structural variation in genomes. Knowledge of genomic structural variation is essential for understanding the evolution of tumours, says Jan Korbel.

Jan Korbel (Photography Thijs Rooimans)

Structural variations (SV), including copy-number variants, inversions and translocations, are responsible for most of the genetic variation in the human genome. Korbel’s group recently developed next-generation DNA sequencing-based approaches (paired-end mapping, split-read analysis and read-depth analysis) for identifying SVs and dissecting the impact of SVs on disease mechanisms, including carcinogenesis. “Those different approaches are crucial in the interpretation of next generation sequencing data,” stresses Korbel.
The techniques are used to construct a high-resolution, population-scale SV map for the 1000 Genomes Project. Korbel explains: “The SV map based on the genomes of over two thousand individuals will enable the delineation of mutational hotspots in the human genome and provide insight into the functional impact as well as the mechanistic origin of SVs.”

Genomic rearrangements

Korbel’s group focuses on unravelling the mechanisms of onset of different kinds of cancer. One of the types of cancer they investigate is paediatric medullablastoma, the most common malignant brain tumour in childhood. So far it was thought that genomic rearrangements occur gradually during tumour development, which may take years. In childhood medullablastomas only few point mutations are commonly observed, and hence it was the question how these few mutations could lead to cancer.
Recently Korbel and his colleagues discovered that massive, complex chromosome rearrangements occur in patients with medullablastomas who had a germline mutation in the p53 tumour suppressor gene. Using in silico models the researchers concluded that the massive rearrangements most likely occurred in a single molecular event, termed chromothripsis. This presumably involves up to hundreds of breaks on a single chromosome, which are then stitched together by the DNA repair machinery.

Crucial link

Chromothripsis typically leads to oncogene amplification in these medulloblastomas. “We don’t know how the p53 mutation leads to chromothripsis, but it is clear that both are causally linked,” says Korbel. “Also in another type of cancer, acute myeloid leukaemia, we found a link between chromothripsis and p53 mutations.”  
Korbel states the clinical relevance of this discovery. “People or families with the p53 mutations have a high risk of developing cancer. Presently the most effective treatment is regular screening for cancers. If tumours are caught early, before metastasis, patients have a significantly increased chance to survive.”

Jan Korbel’s research group at the European Molecular Biology Laboratory (EMBL) in Heidelberg combines experimental and computational approaches for studying genome dynamics, evolution, and structural variation. At NBIC2012 he presented a keynote lecture entitled ‘Genomic structural variation in the germline and in cancer’.

Author: Lilian Vermeer