”Evolution of ipsilateral breast cancer decoded by proteogenomics”
biorxiv(2022)
摘要
Ipsilateral breast tumor recurrence (IBTR) is a clinically important event, where an isolated in-breast recurrence is a potentially curable event but also associated with an increased risk of distant metastases and breast cancer death. It currently remains unclear if IBTRs are associated with molecular changes that can be explored as a resource for precision medicine strategies targeting locally recurring breast cancer. Here, we employed a recently developed proteogenomics workflow to analyze a cohort of 27 primary breast cancers and their matched IBTRs by whole genome sequencing, RNA sequencing, and mass spectrometry-based proteomics to define proteogenomic features of tumor evolution. Analysis of mutational signatures, copy number changes, and cancer specific mutations revealed a relationship with estrogen and progesterone receptor statuses and increased levels of genetic change. This in turn altered the re-programming of the transcriptome and proteome towards a recurring molecular disease phenotype with high replicating capacity and a higher degree of genomic instability possibly enhanced by high expression of APOBEC3B . In conclusion, this study defines how primary breast tumors differentially evolve into different ipsilateral recurrent malignancies depending on their key biomarker status, suggesting that further enhancing the genomic instability in some tumors could serve as an alternative treatment option.
### Competing Interest Statement
PM and MF research contract with PFS Genomics
* AF
: allelic frequency
BC
: breast cancer
CN
: copy number
DIA
: data independent acquisition
DM
: distant metastasis
ER
: estrogen receptor
ERBB2/Her2
: receptor tyrosine-protein kinase erbB-2
FA
: formic acid
FFPE
: formalin-fixed and paraffin-embedded
GSEA
: gene set enrichment analysis
Ki-67
: antigen Ki-67
IBTR
: ipsilateral breast tumor recurrence
IBTRFS
: ipsilateral breast tumor recurrence-free survival
IHC
: immunohistochemistry
IQR
: interquartile range
MS
: mass spectrometry
NBIS
: National bioinformatics infrastructure Sweden
NGI
: national genomics infrastructure
PgR
: progesterone receptor
PoN
: panel of normal
PT
: primary tumor
RNAseq
: RNA sequencing
SNV
: single nucleotide variant
SSBCG
: South Sweden Breast Cancer Group
TP53
: tumor protein p53
UPPMAX
: Uppsala multidisciplinary center for advanced computational science
WGS
: whole genome sequencing.
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关键词
ipsilateral breast cancer,breast cancer
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