Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers
A partir d'échantillons tumoraux prélevés sur 560 patientes atteintes d'un cancer du sein, cette étude identifie notamment 21 sites du génome tumoral sur lesquels des groupes de réarrangements génomiques complexes sont observés de façon récurrente
Background : Complex clusters of rearrangements in cancer genomes are a challenge to interpret. Some are clear amplifications of driver oncogenes but others are less well understood. Detailed analysis of rearrangements within these complex clusters could reveal new insights into selection, and underlying mutational mechanisms. Results : Here, we systematically investigate rearrangements that are densely clustered in individual tumours in a cohort of 560 breast cancers. Applying an agnostic approach, we identify 21 hotspots where clustered rearrangements recur across cancers. Some hotspots coincide with known oncogene loci including CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC. Others contain cancer genes not typically associated with breast cancer: MCL1, PTP4A1 and MYB. Intriguingly, we identify clustered rearrangements that physically connect distant hotspots. In particular, we observe simultaneous amplification of chr8:ZNF703/FGFR1 and chr11:CCND1 where deep analysis reveals that a chr8-chr11 translocation is likely to be an early, critical, initiating event. Conclusions : We present an overview of complex rearrangements in breast cancer, highlighting a potential new way for detecting drivers and revealing novel mechanistic insights into the formation of two common amplicons.
Annals of Oncology 2018