The Life History of 21 Breast Cancers

By S. Nik-Zainal, Peter Van Loo, David C. Wedge, Ludmil B. Alexandrov, Christopher D. Greenman, K. Lau, K. Raine, David Jones, J. Marshall, Manasa Ramakrishna and 39 more. Cell, 2012

1,476 citations recorded by the source corpus.

SUMMARY Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer’s life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer’s lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer’s development, triggering diagnosis.

Subfields: Cancer Research, Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/2d926f467566b26ce64df5ab3e1c54db27e5a16d

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Citations in the corpus

Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution (2014, neutral): “Cluster (n) 1 (60) 2 (23) 3 (15) 4 (14) 5 (13) 6 (11) 7 (9) 8 (6) 9 (5) 10 (5) 11 (3) 12 (3) 13 (2) 14 (2) 15 (1) 16 (1) 17 (1) 18 (1) 19 (1) 20 (1) 0.”
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational-signatures (2017, background): “Twelve consensus base-substitution signatures were identified previously in the 560 breast whole genomes: signatures 1, 2, 3, 5, 6, 8, 13, 17, 18, 20, 26 and 30.”
TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data (2014, background): “Indeed, tumorswith diverse intratumoral patterns of CNA and LOH have been described in breast (Navin et al. 2011; Nik-Zainal et al. 2012), ovarian (Bashashati et al. 2013), renal (Gerlinger et al. 2012, 2014), and brain tumors (Sottoriva et al. 2013).”
Subclonal diversification of primary breast cancer revealed by multiregion sequencing (2015, positive): “Consequently, a given patient’s breast tumor comprises a complex patchwork of genetically related, competing clones 1-3 .”
Pan-cancer patterns of somatic copy-number alteration (2013, background): “A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.”
Chromothripsis and kataegis induced by telomere crisis (2015, neutral): “…represents one of the target substrates for APOBEC enzymes, we hypothesized that the regions caught up in the chromatin bridge would show clusters of point mutations, known as kataegis, analogous to those seen in cancers (Nik-Zainal et al., 2012a; Nik-Zainal et al., 2012b; Roberts et al., 2012).”