Paper - Review
10.1016/j.cell.2019.05.013
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