Mutational Processes Molding the Genomes of 21 Breast Cancers

Nik-Zainal, Serena; Alexandrov, Ludmil B.; Wedge, David C.; Loo, Peter Van; Greenman, Christopher; Raine, Keiran; Jones, David R.; Hinton, Jonathan; Marshall, John; Stebbings, Lucy; Menzies, Andrew; Martin, Sancha; Leung, Kenric; Chen, Lina; Leroy, Catherine; Ramakrishna, Manasa; Rance, Richard; Lau, King Wai; Mudie, Laura; Varela, Ignacio; McBride, David J.; Bignell, Graham R.; Cooke, Susanna L.; Shlien, Adam; Gamble, John; Whitmore, Ian; Maddison, Mark; Tarpey, Patrick; Davies, Helen; Papaemmanuil, Elli; Stephens, Philip J.; McLaren, Stuart; Butler, Adam; Teague, Jon W.; Jönsson, Göran; Garber, Judy E.; Silver, Daniel P.; Miron, Penelope; Fatima, Aquila; Boyault, Sandrine; Langerød, Anita; Tutt, Andrew; Martens, John W.M.; Aparicio, Samuel; Borg, Åke; Vincent‐Salomon, Anne; Thomas, Gilles; Børresen‐Dale, Anne‐Lise; Richardson, Andrea L.; Neuberger, Michael S.; Futreal, P. Andrew; Campbell, Peter J.; Stratton, Michael R.

doi:10.1016/j.cell.2012.04.024

Cited by 1,716 publications

(2,032 citation statements)

References 62 publications

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“…The C4T:G4A alteration forms a major part of three of the five mutational signatures identified in breast cancer 35 and is thought to occur through the spontaneous deamination of 5-methyl-cytosine which accumulates with age 35,36 and overactivity of the APOBEC family of cytidine deaminases. 35,37 Although C4T:G4A alterations are also characteristic of formalin-related DNA damage 18 the proportion of C4T:G4A alterations is similar to that reported in fresh-frozen samples of invasive breast cancer (~40%) 4 and DCIS (~50%) 14,15 , so the C4T: G4A alterations detected are unlikely to represent formalin-fixation artefacts.…”

Section: Discussionsupporting

confidence: 69%

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n = 20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P = 0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P = 0.005), including a significant positive association with amplification or gain of ERBB2 (Po 0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P = 0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.

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Section: Discussionsupporting

confidence: 69%

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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“…Hypothesizing that the abundance of mutated genes is a measure of genetic heterogeneity of the tumour 34, we here provide evidence that particularly pathological grading of breast cancer is in fact a microscopic read‐out of tumour heterogeneity, which indicates different biological and clinical behaviour of the tumour. Several studies either sequencing tumour bulks or single tumour cells have demonstrated that breast cancer subtypes exhibit considerable spatial and temporal heterogeneity on the genetic level within the primary, during metastatic progression and in patient‐derived xenografts 24, 25, 26, 27, 28, 29, 30, 31. This genomic diversity within breast cancers is a result of but also facilitates cellular evolution 34 allowing the tumour to dynamically adapt to external or internal stimuli as originally conceptualized by Nowell in 1976 54.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent genomic profiling studies 24, 25, 26, 27, 28, 29, 30, 31 suggested a substantial degree of intra‐ and inter‐tumour heterogeneity fuelling selection processes during evolution of breast cancer 32, 33, which may complicate prognostication as well as prediction and impede cancer precision medicine approaches 34. In this context, it is worth recalling that just as the molecular phenotype, the morphological phenotype of the tumour, including tumour grade and tumour size is essentially a result of accumulated genetic aberrations over time, thereby reflecting tumour evolution at the phenotypic level.…”

Section: Introductionmentioning

confidence: 99%

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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“…In the past few years, there are 30 patterns of mutational signatures be found across the spectrum of human cancer types from many large‐scale analyses,43, 44, 45, 46, 47 including 11 types of signatures found in gastric cancer. We observed a significant association between rs1679709 and the weights of COSMIC Signature 15.…”

Section: Discussionmentioning

confidence: 99%

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

et al. 2018

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Genome‐wide association studies have identified several germline variants in gastric cancer. Meanwhile, sequencing studies have characterized extensive somatic alterations that arise during gastric carcinogenesis. However, the relationship between the germline variants and somatic alterations is still unclear in gastric cancer. A total of 11 susceptibility loci and 276 driver genes of gastric cancer were determined based on previous studies and publicly available database. An enrichment analysis was made to detect whether driver genes were enriched in susceptibility regions. Besides, we performed a pathway enrichment analysis to find common‐enrich pathways of cancer driver genes and susceptibility genes. Finally, on the basis of the gastric cancer samples and data from TCGA STAD project, we evaluated the associations between susceptibility loci and somatic alterations. Enrichment analysis showed that gastric cancer susceptibility genes were more likely to be enriched in driver genes than in all the genes (P = .05). The susceptibility genes and driver genes were commonly enriched in 8 biological pathways. Gastric cancer susceptibility locus of rs2285947 was associated with truncation mutation within Signaling by PDGF pathway (OR = 0.26, 95%CI: 0.12‐0.55, P = 3.93 × 10−4). The rs1679709 was connected with COSMIC Signature15 (P = .026). Moreover, rs1679709 was also associated with copy number values of RFC4 which is related to Signature15. These results provide evidence for the relationship between germline variants and somatic alterations, which facilitate understanding the interactive mechanism of germline variations with somatic alterations in gastric cancer development.

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Mutational Processes Molding the Genomes of 21 Breast Cancers

Cited by 1,716 publications

References 62 publications

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

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

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

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