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Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic

Yang Yang1, Michelle L Badura2,3, Patrick C O'Leary2

  • 1Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.

Nature Cancer
|November 18, 2024
PubMed

Insights

Large tandem duplications in cancer are linked to transcription-replication collisions (TRCs). These genomic events, identified in over 6,000 tumors, can serve as biomarkers for patient prognosis and treatment strategies.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Mechanisms

Background:

  • Somatic structural variations (SVs) are abundant in cancer, but their formation mechanisms are not fully understood.
  • Genome instability is a hallmark of cancer, driven by various molecular processes.

Purpose of the Study:

  • To investigate the role of transcription and DNA replication collisions in the formation of SVs, specifically large tandem duplications (TDs).
  • To identify potential biomarkers for cancer prognosis and treatment based on SV signatures.

Main Methods:

  • Analysis of whole-genome sequencing data from 6,193 tumors across three independent pan-cancer cohorts.
  • Deconvolution of SV signatures to identify patterns associated with transcription-replication collisions (TRCs).
  • Functional studies involving CDK12 inactivation and inhibition of key cell cycle regulators (WEE1, CHK1, ATR).

Main Results:

  • A transcription-dependent, replicated-strand bias, indicative of TRCs, was detected in large TDs.
  • Large TDs are prevalent in specific cancers (female-enriched, upper GI, prostate) and correlate with poor survival and mutations in TP53, CDK12, and SPOP.
  • CDK12 inactivation led to increased TRCs, R-loops, and large TDs, while WEE1, CHK1, and ATR inhibition selectively impacted CDK12-deficient cells.

Conclusions:

  • Large TDs in cancer likely arise from TRCs.
  • The presence of large TDs can serve as a prognostic biomarker.
  • Targeting WEE1, CHK1, and ATR may be a therapeutic strategy for cancers with CDK12 deficiency and associated large TDs.

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