Genomic instability — an evolving hallmark of cancer

Negrini, Simona; Gorgoulis, Vassilis G.; Halazonetis, Thanos D.

doi:10.1038/nrm2858

Cited by 1,921 publications

(1,662 citation statements)

References 60 publications

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“…However, we identified five mutated genes ( TP53 , NCOR1 , PTRD , NF1 and RB1 ), which showed strong associations to high numbers of mutated genes independent of the tumour subtype. As expected, non‐silent mutations in TP53 and RB1, which have been causally linked to genomic instability of tumours 46, 47, are strongly correlated with the number of mutated genes in breast cancer. Moreover, our data show that high numbers of mutated genes are strongly associated with mutant NCOR1 , which is mutated in ∼4% of breast cancer cases 2.…”

Section: Discussionsupporting

confidence: 78%

Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies

Bockmayr

Denkert

et al. 2015

The Journal of Pathology CR

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Breast cancer is a complex molecular disease comprising several biological subtypes. However, daily routine diagnosis is still based on a small set of well‐characterized clinico‐pathological variables. Here, we try to link the two worlds of surgical pathology and multilayered molecular profiling by analyzing the relationships between clinico‐pathological phenotypes and mutational loads of breast cancer. We evaluated the number of mutated genes with somatic non‐silent mutations in different subgroups of breast cancer based on clinico‐pathological, including immunohistochemical and tumour characteristics. The analysis was performed for a cohort of 687 primary breast cancer patients with mutational profiling, gene expression and clinico‐pathological data available from The Cancer Genome Atlas (TCGA) project. The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e−14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e−10 and p = 4.3e−10, respectively). We observed significant associations (|R| > 0.4) between the abundance of mutated genes and expression levels of genes related to proliferation in the overall cohort and hormone receptor positive cohort, including the Recurrence Score gene signature (e.g., MYBL2 and BIRC5). Specific mutated genes (TP53, NCOR1, NF1, PTPRD and RB1) were highly significantly associated with high loads of mutated genes. Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 – 20.0, p = 0.044). Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer. We provide evidence that specific levels of the mutational load underlie different morphological and biological phenotypes, which collectively constitute the current basis of pathological diagnosis. Our study is a step towards genomics‐informed breast pathology and will provide a basis for future studies in this field bridging the gap between morphology, tumour biology and medical oncology.

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Section: Discussionsupporting

confidence: 78%

Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies

Bockmayr

Denkert

et al. 2015

The Journal of Pathology CR

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“…9,10 RAF fusions are present in about 2% of CaP associated with aggressive disease. 10 Earlier, other genes such as p53, [11][12][13] AR, 14,15 AKT/PTEN, 16 EZH2, 17 SPINK, 18 ETV1 9,19 have been shown to be associated with subsets of progressive CaP, however their use as prognostic markers in clinical setting needs to be streamlined. SPARC (secreted protein, acidic, rich in cysteine) is a secreted glycoprotein that supports the migration of CaP cells to bone and demonstrates increased expression in CaP metastatic foci and cell lines.…”

Section: Introductionmentioning

confidence: 99%

Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression

DeRosa

Furusato

Shaheduzzaman

et al. 2011

Prostate Cancer Prostatic Dis

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“…The current effort to sequence thousands of samples in 50 tumour types would ascertain whether the observations of this study are general for all cancer types 11 . Second, we would like to conduct a systematic dissection of how mutational heterogeneity is influenced by multiple factors, such as the tissue type, exposure to mutagens, age of the host, and so on 36 . Particularly, do differences in the mutational process lead to different evolutionary paths and different clinical outcomes?…”

Section: Discussionmentioning

confidence: 99%

DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes

2012

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Cancer cells evolve from normal cells by somatic mutations and natural selection. Comparing the evolution of cancer cells and that of organisms can elucidate the genetic basis of cancer. Here we analyse somatic mutations in > 400 cancer genomes. We find that the frequency of somatic single-nucleotide variations increases with replication time during the s phase much more drastically than germ-line single-nucleotide variations and somatic large-scale structural alterations, including amplifications and deletions. The ratio of nonsynonymous to synonymous single-nucleotide variations is higher for cancer cells than for germ-line cells, suggesting weaker purifying selection against somatic mutations. Among genes with recurrent mutations only cancer driver genes show evidence of strong positive selection, and late-replicating regions are depleted of cancer driver genes, although enriched for recurrently mutated genes. These observations show that replication timing has a prominent role in shaping the single-nucleotide variation landscape of cancer cells.

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Genomic instability — an evolving hallmark of cancer

Cited by 1,921 publications

References 60 publications

Classical pathology and mutational load of breast cancer – integration of two worlds

Classical pathology and mutational load of breast cancer – integration of two worlds

Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression

DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes

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