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- Aine, Mattias, et al.
(författare)
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Molecular analyses of triple-negative breast cancer in the young and elderly
- 2021
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in younger versus older patients represent similar or different molecular diseases in the context of genetic and transcriptional subtypes and immune cell infiltration.PATIENTS AND METHODS: In total, 237 patients from a reported population-based south Swedish TNBC cohort profiled by RNA sequencing and whole-genome sequencing (WGS) were included. Patients were binned in 10-year intervals. Complimentary PD-L1 and CD20 immunohistochemistry and estimation of tumor-infiltrating lymphocytes (TILs) were performed. Cases were analyzed for differences in patient outcome, genomic, transcriptional, and immune landscape features versus age at diagnosis. Additionally, 560 public WGS breast cancer profiles were used for validation.RESULTS: Median age at diagnosis was 62 years (range 26-91). Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy. Among the BRCA1-deficient cases (82/237), 90% were diagnosed before the age of 70 and were predominantly of the basal-like subtype. In the full TNBC cohort, reported associations of patient age with changes in Ki67 expression, PIK3CA mutations, and a luminal androgen receptor subtype were confirmed. Within DNA repair deficiency or gene expression defined molecular subgroups, age-related alterations in, e.g., overall gene expression, immune cell marker gene expression, genetic mutational and rearrangement signatures, amount of copy number alterations, and tumor mutational burden did, however, not appear distinct. Similar non-significant associations for genetic alterations with age were obtained for other breast cancer subgroups in public WGS data. Consistent with age-related immunosenescence, TIL counts decreased linearly with patient age across different genetic TNBC subtypes.CONCLUSIONS: Age-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology.
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- Akdemir, KC, et al.
(författare)
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Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer
- 2020
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 294-
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Tidskriftsartikel (refereegranskat)abstract
- Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.
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- Alexandrov, Ludmil B, et al.
(författare)
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The repertoire of mutational signatures in human cancer
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578:7793, s. 94-101
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3-15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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- Andersson, Alma, et al.
(författare)
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Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases. While transcriptomics have enhanced our understanding for cancer, spatial transcriptomics enable the characterisation of cellular interactions. Here, the authors integrate single cell data with spatial information for HER2 + tumours and develop tools for the prediction of interactions between tumour-infiltrating cells.
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| 7. |
- Andersson, Alma, et al.
(författare)
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Spatial Deconvolution of HER2-positive Breast Tumors Reveals Novel Intercellular Relationships
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra-and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. We integrate and spatially map tumor-associated types from single cell data to find: segregated epithelial cells, interactions between B and T-cells and myeloid cells, co-localization of macrophage and T-cell subsets. A model is constructed to infer presence of tertiary lymphoid structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define novel interactions between tumor-infiltrating cells in breast cancer and provide tools generalizing across tissues and diseases.
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- Bengtsson, Ylva, et al.
(författare)
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Serum copper, zinc and copper/zinc ratio in relation to survival after breast cancer diagnosis: A prospective multicenter cohort study
- 2023
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Ingår i: Redox Biology. - 2213-2317. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe essential trace elements copper and zinc, and their ratio (copper/zinc), are important for maintaining redox homeostasis. Previous studies suggest that these elements may impact breast cancer survival. However, no epidemiological study has so far been conducted on the potential association between copper and copper/zinc levels and survival after breast cancer diagnosis. In this study, we aimed to examine the relationship between serum copper, zinc and copper/zinc levels and survival following breast cancer diagnosis.Patients and methodsThe Sweden Cancerome Analysis Network – Breast Initiative (SCAN-B) is a population-based cohort study including multiple participating hospitals in Sweden. A total of 1998 patients diagnosed with primary invasive breast cancer were followed for approximately nine years. Serum levels of copper and zinc and their ratio at the time of diagnosis was analyzed in relation to breast cancer survival using multivariate Cox regression, yielding hazard ratios (HR) with 95% confidence intervals.ResultsA higher copper/zinc ratio was associated with lower overall survival after breast cancer diagnosis. Comparing patients with a copper/zinc ratio in quartile 4 vs 1, the crude HR was 2.29 (1.65–3.19) (Ptrend ConclusionThere is evidence that the serum copper/zinc ratio provides an independent predictive value for overall survival following breast cancer diagnosis.
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| 10. |
- Bhandari, Vinayak, et al.
(författare)
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Divergent mutational processes distinguish hypoxic and normoxic tumours
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.
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