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New concepts in breast cancer genomics and genetics.

Goncalves R, Warner WA, Luo J, Ellis MJ - Breast Cancer Res. (2014)

Bottom Line: In this review, we consider progress largely from the perspective of new concepts and hypotheses raised so far.Finally, we address the challenge of extracting medical value from genomic data.A weakness of many datasets is inadequate clinical annotation, which hampers the establishment of links between the mutation spectra and the efficacy of drugs or disease phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Program, Department of Medical Oncology, Washington University School of Medicine, 660 S. Euclid Ave, St Louis 63110, MO, USA; Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave, St Louis 63110, MO, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, 320A Cullen MS600, Houston 77030, TX, USA.

ABSTRACT
Massively parallel DNA and RNA sequencing approaches have generated data on thousands of breast cancer genomes. In this review, we consider progress largely from the perspective of new concepts and hypotheses raised so far. These include challenges to the multistep model of breast carcinogenesis and the discovery of new defects in DNA repair through sequence analysis. Issues for functional genomics include the development of strategies to differentiate between mutations that are likely to drive carcinogenesis and bystander background mutations, as well as the importance of mechanistic studies that examine the role of mutations in genes with roles in splicing, histone methylation, and long non-coding RNA function. The application of genome-annotated patient-derived breast cancer xenografts as a potentially more reliable preclinical model is also discussed. Finally, we address the challenge of extracting medical value from genomic data. A weakness of many datasets is inadequate clinical annotation, which hampers the establishment of links between the mutation spectra and the efficacy of drugs or disease phenotypes. Tools such as dGene and the DGIdb are being developed to identify possible druggable mutations, but these programs are a work in progress since extensive molecular pharmacology is required to develop successful ‘genome-forward’ clinical trials. Examples are emerging, however, including targeting HER2 in HER2 mutant breast cancer and mutant ESR1 in ESR1 endocrine refractory luminal-type breast cancer. Finally, the integration of DNA- and RNA-based sequencing studies with mass spectrometry-based peptide sequencing and an unbiased determination of post-translational modifications promises a more complete view of the biochemistry of breast cancer cells and points toward a new discovery horizon in our understanding of the pathophysiology of this complex disease.

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Related in: MedlinePlus

The presence of translocations and amplification at the ends of the breakpoints is evidence of chromothripsis in this Circos plot from a breast cancer sample. Chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe.
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Fig1: The presence of translocations and amplification at the ends of the breakpoints is evidence of chromothripsis in this Circos plot from a breast cancer sample. Chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe.

Mentions: Aside from the focus on the identification of individual genes that are repetitively disrupted in breast cancer, a more broad-based analysis of breast cancer genome structures has led to a paradigm shift in the way we view pathogenesis. The standard multistep model of carcinogenesis postulates that mutations accumulate gradually, one at a time, in a process of Darwinian selection in which individual mutant-bearing clones effectively compete with normal cells and other clones within the tumor through the acquisition of the ability to transform, invade, metastasize, and evade drug treatment [17]. However, it was recently demonstrated that multiple mutations can arise over a very short period wherein multiple chromosomal breaks that occurred during a single catastrophic cell division event are (rarely) viably repaired, reshuffling the genome in a way that rapidly triggers transformation though the simultaneous oncogene amplifications and tumor suppressor gene deletions in the vicinity of the multiple translocations that ensue (chromothripsis) [18] (Figure 1). The reported frequency of chromothripsis in breast cancer varies from 2% to 11.06% [18],[19]. Since chromothripsis and interval breast cancer are both marked by the suddenness of their appearance, we hypothesize that chromothripsis might explain the development of rapidly progressing, so-called ‘interval’, breast cancers that arise suddenly between screening visits. For this class of tumors, screening could never be effective as the time span of tumor development is too short. The genomic structure of interval breast cancers should be pursued aggressively as these tumors carry a high mortality burden. As more patients are included in clinical trials that include longitudinal genome sequencing of tumor samples, this hypothesis will be tested in the near future.Figure 1


New concepts in breast cancer genomics and genetics.

Goncalves R, Warner WA, Luo J, Ellis MJ - Breast Cancer Res. (2014)

The presence of translocations and amplification at the ends of the breakpoints is evidence of chromothripsis in this Circos plot from a breast cancer sample. Chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384360&req=5

Fig1: The presence of translocations and amplification at the ends of the breakpoints is evidence of chromothripsis in this Circos plot from a breast cancer sample. Chromothripsis scars the genome when localized chromosome shattering and repair occur in a one-off catastrophe.
Mentions: Aside from the focus on the identification of individual genes that are repetitively disrupted in breast cancer, a more broad-based analysis of breast cancer genome structures has led to a paradigm shift in the way we view pathogenesis. The standard multistep model of carcinogenesis postulates that mutations accumulate gradually, one at a time, in a process of Darwinian selection in which individual mutant-bearing clones effectively compete with normal cells and other clones within the tumor through the acquisition of the ability to transform, invade, metastasize, and evade drug treatment [17]. However, it was recently demonstrated that multiple mutations can arise over a very short period wherein multiple chromosomal breaks that occurred during a single catastrophic cell division event are (rarely) viably repaired, reshuffling the genome in a way that rapidly triggers transformation though the simultaneous oncogene amplifications and tumor suppressor gene deletions in the vicinity of the multiple translocations that ensue (chromothripsis) [18] (Figure 1). The reported frequency of chromothripsis in breast cancer varies from 2% to 11.06% [18],[19]. Since chromothripsis and interval breast cancer are both marked by the suddenness of their appearance, we hypothesize that chromothripsis might explain the development of rapidly progressing, so-called ‘interval’, breast cancers that arise suddenly between screening visits. For this class of tumors, screening could never be effective as the time span of tumor development is too short. The genomic structure of interval breast cancers should be pursued aggressively as these tumors carry a high mortality burden. As more patients are included in clinical trials that include longitudinal genome sequencing of tumor samples, this hypothesis will be tested in the near future.Figure 1

Bottom Line: In this review, we consider progress largely from the perspective of new concepts and hypotheses raised so far.Finally, we address the challenge of extracting medical value from genomic data.A weakness of many datasets is inadequate clinical annotation, which hampers the establishment of links between the mutation spectra and the efficacy of drugs or disease phenotypes.

View Article: PubMed Central - PubMed

Affiliation: Breast Cancer Program, Department of Medical Oncology, Washington University School of Medicine, 660 S. Euclid Ave, St Louis 63110, MO, USA; Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Ave, St Louis 63110, MO, USA; Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, 320A Cullen MS600, Houston 77030, TX, USA.

ABSTRACT
Massively parallel DNA and RNA sequencing approaches have generated data on thousands of breast cancer genomes. In this review, we consider progress largely from the perspective of new concepts and hypotheses raised so far. These include challenges to the multistep model of breast carcinogenesis and the discovery of new defects in DNA repair through sequence analysis. Issues for functional genomics include the development of strategies to differentiate between mutations that are likely to drive carcinogenesis and bystander background mutations, as well as the importance of mechanistic studies that examine the role of mutations in genes with roles in splicing, histone methylation, and long non-coding RNA function. The application of genome-annotated patient-derived breast cancer xenografts as a potentially more reliable preclinical model is also discussed. Finally, we address the challenge of extracting medical value from genomic data. A weakness of many datasets is inadequate clinical annotation, which hampers the establishment of links between the mutation spectra and the efficacy of drugs or disease phenotypes. Tools such as dGene and the DGIdb are being developed to identify possible druggable mutations, but these programs are a work in progress since extensive molecular pharmacology is required to develop successful ‘genome-forward’ clinical trials. Examples are emerging, however, including targeting HER2 in HER2 mutant breast cancer and mutant ESR1 in ESR1 endocrine refractory luminal-type breast cancer. Finally, the integration of DNA- and RNA-based sequencing studies with mass spectrometry-based peptide sequencing and an unbiased determination of post-translational modifications promises a more complete view of the biochemistry of breast cancer cells and points toward a new discovery horizon in our understanding of the pathophysiology of this complex disease.

Show MeSH
Related in: MedlinePlus