Paper - Review

DOI: 10.1016/j.cell.2019.05.013

Graphical Abstract

In Brief

Driver fusion oncogenes
← in human lung adenocarcinoma of non-smokers
→ are generated ← from complex genomic rearrangements
→ often arise ← in early decades of life
← long before diagnosable disease

Highlights

Driver fusion oncogenes
← in LADCs
→ are generated ← from complex genomic rearrangements

These rearrangements
→ are frequently copy-number balanced
∴ resembling germ-line events

Fusions
→ arise ← in early decades of life
→ leaving long latency → to diagnosis

SETD2 inactivation
→ is cooperative ← with fusion oncogenes
← in TP53-wild-type LADCs

Summary

Mutational processes
← giving rise → to lung adenocarcinomas
← in non-smokers
→ remains elusive

Analyzed → 138 LADC whole genomes
← including 83 cases ← with minimal contribution of (smoking-associated mutational signature)

Genomic rearrangements
→ were NOT correlated ← with smoking-associated mutations
→ frequently served ← as driver events of smoking-signature-low LADCs

Complex genomic rearrangements
← including 1⃣ chromathripsis 2⃣ chromoplexy
→ generated 74% of known fusion oncogenes
← including 1⃣ EML4-ALK 2⃣ CD74-ROS1 3⃣ KIF5B-RET

These fusion-oncogene-associated rearrangements
→ were frequently copy-number-balanced
∴ A genomic signature of early oncogenesis

Fusions & point mutations
← of canonical oncogenes
→ were often acquired ← in the early decades of life
∵ Analysis of mutation timing

Cancer-related genes
→ were disrupted & amplified
← by complex rearrangements

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