The Life History of 21 Breast Cancers

Nik-Zainal, Serena; Loo, Peter Van; Wedge, David C.; Alexandrov, Ludmil B.; Greenman, Christopher; Lau, Ka-Yi; Jones, Dee; Marshall, J; Ramakrishna, Manasa; Cooke, Susanna L.; Hinton, Jamie; Menzies, Alexander M.; Leroy, Cédric; Jia, Minghan; Rance, Richard; Mudie, Laura; Gamble, Stephen J.; Stephens, Phil; Tarpey, Patrick; Papaemmanuil, Elli; Davies, HD; Varela, Ignacio; McBride, D.J.; Bignell, Graham R.; Leung, Ka‐Ho; Butler, A P; Teague, John; Martin, S; Jonsson, Gösta; Mariani, Odette; Boyault, Sandrine; Miron, Penelope; Fatima, Arooj; Langerød, Anita; Sajr., Aparicio; Tutt, Alison; Sieuwerts, AM; Borg, Alexander; Thomas, Gareth M.; Vincent‐Salomon, Anne; Richardson, A; Børresen‐Dale, Anne‐Lise; Futreal, P. Andy; Stratton, M.R.; Campbell, P J

doi:10.1016/j.cell.2015.07.039

Cited by 74 publications

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“…In this context, the fittest clones are selected for during the metastatic process or via external selective pressures (e.g., administration of systemic therapeutics) [2,7]. In breast cancer, evolutionary studies have focused thus far on analyses of the relationship between primary tumors and metastatic deposits, and within and between metastatic deposits [2,4,8], and on subclone evolution [4,9]. The recent analysis of Newburger et al [6] focused instead on the origins of breast cancer and its evolution.…”

Section: Intra-tumor Genetic Heterogeneitymentioning

confidence: 97%

The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets

et al. 2014

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Breast cancers and most malignant tumors are composed of heterogeneous tumor cells both at genetic and morphological levels; intra-tumor heterogeneity can be one underlying cause of therapeutic resistance. Classical studies have focused on analyses of the relationship between primary tumors and metastatic dissemination, and on subclone evolution. However, it should be noted that tumor heterogeneity at the level of protein expression (proteomics) has not been yet studied in depth. The differences in protein expression also can play an important role in elucidating the relationship between intra-tumor heterogeneity and resistance to systemic therapy. In fact, in human tumors there is not always a homogeneous expression of many of the crucial factors involved in cell signaling, such as pMAPK, pAKt, pMTOR, even with constitutive oncogenic alterations upstream, such as HER2, PI3 K. Conversely, two of these factors, peIF4E and p4E-BP1, which are downstream, and control protein translation, show a diffuse and strong protein expression. In summary, most of cell signaling factors show a heterogeneous expression, regardless of oncogenic alterations. Tissue heterogeneity could be driven by local factors, including hypoxia. The fact that the phosphorylation of crucial proteins such as 4E-BP1 and eIF4E is observed homogeneously throughout most tumors and are druggable opens the chance to get real potential targets in cancer therapy.

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Section: Intra-tumor Genetic Heterogeneitymentioning

confidence: 97%

The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets

et al. 2014

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“…However, as reported by Navin et al [10], Nik-Zainal et al [6], and Shah et al [7], the number of pattern in these complicated genomic rearrangements was not so large that accumulation of these kinds of abnormalities looks punctuated but not gradual.…”

Section: Genomic Tumor Evolution Inferred From Primary Breast Tumormentioning

confidence: 60%

“…By reading the mixed DNA sample deeply using NGS, an accurate proportion of each genomic mutation can be estimated. It was further possible to distinguish intra-tumoral clonal components, in combination with the development of new clonality analysis algorithms, some of which adopted a hypothesis that genomic abnormalities in common to the same cancer cell clones are supposed to have similar mutation rates [6,7].…”

Section: Genomic Analysis Methods and Tumor Evolution Researchmentioning

confidence: 99%

“…In 2012, Nik-Zainal et al [6] and Shah et al [7] conducted deep genomic sequencing of 21 breast tumors and 104 triple-negative breast cancers (TNBCs), respectively, and inferred genomic tumor clones according to mutation patterns. In both papers, very deep sequencing enabled determination of accurate frequency of each mutation, and the number of clones as well as the order of their appearance were estimated by analyzing complicated pattern of the mutation frequencies and genomic localization of mutations.…”

Section: Genomic Tumor Evolution Inferred From Primary Breast Tumormentioning

confidence: 99%

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Genomic tumor evolution of breast cancer

Sato

Toi

2015

Breast Cancer

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Owing to recent technical development of comprehensive genome-wide analysis such as next generation sequencing, deep biological insights of breast cancer have been revealed. Information of genomic mutations and rearrangements in patients' tumors is indispensable to understand the mechanism in carcinogenesis, progression, metastasis, and resistance to systemic treatment of breast cancer. To date, comprehensive genomic analyses illustrate not only base substitution patterns and lists of driver mutations and key rearrangements, but also a manner of tumor evolution. Breast cancer genome is dynamically changing and evolving during cancer development course from non-invasive disease via invasive primary tumor to metastatic tumor, and during treatment exposure. The accumulation pattern of base substitution and genomic rearrangement looks gradual and punctuated, respectively, in analogy with contrasting theories for evolution manner of species, Darwin's phyletic gradualism, and Eldredge and Gould's "punctuated equilibrium". Liquid biopsy is a non-invasive method to detect the genomic evolution of breast cancer. Genomic mutation patterns in circulating tumor cells and circulating cell-free tumor DNA represent those of tumors existing in patient body. Liquid biopsy methods are now under development for future application to clinical practice of cancer treatment. In this article, latest knowledge regarding breast cancer genome, especially in terms of 'tumor evolution', is summarized.

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“…Mutation signatures can differ depending on the length of exposure, leading to alterations in drug response, and the number of mutations can also vary considerably between patients and tumour types. Whole genome sequencing may provide insight into the molecular mechanisms underlying these mutations [15,16], and the advent of next-generation sequencing (NGS) has meant that such analysis is now becoming available in academic hospitals. However, interpretation of NGS findings is complex since the technique cannot define the prevalence of particular mutations nor make any inference of their predictive values.…”

Section: Current Challenges In Translational Oncologymentioning

confidence: 99%

Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development

Stahel

Bogaerts

Ciardiello

et al. 2015

Cancer Treatment Reviews

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Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer.

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The Life History of 21 Breast Cancers

Abstract: The original author list of this Preview included a formatting error that has been corrected in the list above and with the Preview online.924 Cell 162, 924, August 13, 2015 ª2015 Elsevier Inc.

Cited by 74 publications

References 0 publications

The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets

The intra-tumor heterogeneity of cell signaling factors in breast cancer: p4E-BP1 and peIF4E are diffusely expressed and are real potential targets

Genomic tumor evolution of breast cancer

Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development

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