Clonal Evolution Patterns In Relapsed Acute Myeloid Leukaemia Revealed By Whole-Genome Sequencing.pdf

Summary:

This letter reports a comprehensive study using whole-genome sequencing to investigate clonal evolution in relapsed acute myeloid leukaemia (AML). Researchers analyzed primary tumor and relapse genomes from eight AML patients, discovering:

1. Novel Mutations: Identified several novel, recurrently mutated genes in AML, including WAC, SMC3, DIS3, DDX41, and DAXX.
2. Clonal Evolution Patterns: Observed two main patterns of clonal evolution during AML relapse:
- The founding clone gains mutations and evolves into the relapse clone.
- A subclone of the founding clone survives initial therapy, accumulates additional mutations, and expands at relapse.
3. Chemotherapy Impact: Chemotherapy failed to eradicate the founding clone in all cases, suggesting that relapse is associated with new mutations and clonal evolution shaped by chemotherapy.
4. Relapse-Specific Mutations: Noted an increase in transversions, likely due to DNA damage caused by cytotoxic chemotherapy.

Methods:

- Whole-genome sequencing was performed on primary tumor–relapse pairs and matched skin samples from eight patients.
- Deep sequencing of captured target DNAs from skin, primary tumor, and relapse tumor specimens yielded a median of 590-fold coverage per site.
- A total of 169 tier 1 coding mutations were identified across the eight patients, with 19 being relapse-specific.

Conclusion:

The study provides valuable insights into the genetic changes associated with AML relapse and highlights the role of clonal evolution in treatment resistance. These findings have implications for developing more effective therapies targeted at specific clonal populations.