Cancer • March 30, 2023, 8:51 a.m.

Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures
Medulloblastoma is a type of cancer that affects the brain and spinal cord. It is particularly dangerous because it can spread rapidly and is often resistant to treatment. However, recent breakthroughs in long-read sequencing technology have revealed new insights into the genetic and epigenetic landscape of medulloblastoma, potentially opening up new avenues for diagnosis and treatment.

According to a recent study, cancer genomes contain a wide range of structural variants that are crucial to driving tumorigenesis. However, many of these variants may go undetected in traditional short-read sequencing methods. This is where long-read sequencing, such as that offered by Oxford Nanopore Technologies (ONT), comes in. By providing a more comprehensive view of the genome, long-read sequencing can help researchers to unravel the complex genetic and epigenetic landscape of medulloblastoma.

In the study, researchers used long-read sequencing to analyze paired diagnostic and post-therapy medulloblastoma samples. What they found was a range of complex rearrangements and structural variants that had previously gone undetected. These included a 1.55 Megabasepair chromothripsis event, in which multiple genomic segments are shattered and then stitched back together in a scrambled order.

Perhaps even more intriguingly, the researchers also uncovered a new type of structural variant that they termed "templated insertion thread". This pattern involves short insertions of genetic material that self-concatenate into highly amplified structures of up to 50kbp in size. Templated insertion threads were found to occur in 3% of cancers, with a prevalence ranging up to 74% in liposarcoma, and were often associated with chromothripsis.

In addition to its potential for identifying structural variants, long-read sequencing can also be used to profile the methylome, or the pattern of DNA methylation across the genome. In the medulloblastoma study, researchers found allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in seven cancer-driver genes.

Taken together, these findings suggest that long-read sequencing has tremendous potential for improving our understanding of medulloblastoma and other types of cancer. By providing a more complete view of the genome and epigenome, long-read sequencing could help to identify new diagnostic and therapeutic targets that have previously gone undetected. As researchers continue to refine and improve this technology, we may be able to unlock the secrets of cancer once and for all.

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