Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers

TY - JOUR

T1 - Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers

AU - Glodzik, D.

AU - Purdie, C.

AU - Rye, I. Hansine

AU - Simpson, P.

AU - Staaf, J.

AU - Span, P. N.

AU - Russnes, H.

AU - Nik-Zainal, S.

N1 - This work is funded by a Wellcome Trust Strategic Award (101126/B/13/Z). DG was supported by the EU-FP7-SUPPRESSTEM project and subsequently by Lund University. SN-Z is funded by CRUK Advanced Clinician Scientist Award (C60100/A23916).

PY - 2018/11

Y1 - 2018/11

N2 - Background: Complex clusters of rearrangements are a challenge in interpretation of cancer genomes. Some clusters of rearrangements demarcate clear amplifications of driver oncogenes but others are less well understood. A detailed analysis of rearrangements within these complex clusters could reveal new insights into selection and underlying mutational mechanisms.Patients and methods: 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.Results: 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.

AB - Background: Complex clusters of rearrangements are a challenge in interpretation of cancer genomes. Some clusters of rearrangements demarcate clear amplifications of driver oncogenes but others are less well understood. A detailed analysis of rearrangements within these complex clusters could reveal new insights into selection and underlying mutational mechanisms.Patients and methods: 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.Results: 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.

KW - breast cancer

KW - genome

KW - rearrangements

KW - mutational mechanism

KW - selection

KW - amplification

UR - https://www.scopus.com/pages/publications/85058602269

U2 - 10.1093/annonc/mdy404

DO - 10.1093/annonc/mdy404

M3 - Article

C2 - 30252041

SN - 0923-7534

VL - 29

SP - 2223

EP - 2231

JO - Annals of Oncology

JF - Annals of Oncology

IS - 11

ER -