Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. ...Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.
The oncogenic miR-155 is upregulated in many human cancers, and its expression is increased in more aggressive and therapy-resistant tumors, but the molecular mechanisms underlying miR-155-induced ...therapy resistance are not fully understood. The main objectives of this study were to determine the role of miR-155 in resistance to chemotherapy and to evaluate anti-miR-155 treatment to chemosensitize tumors.
We performed
studies on cell lines to investigate the role of miR-155 in therapy resistance. To assess the effects of miR-155 inhibition on chemoresistance, we used an
orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy. To analyze the association of miR-155 expression and the combination of miR-155 and
expression with cancer survival, we studied 956 patients with lung cancer, chronic lymphocytic leukemia, and acute lymphoblastic leukemia.
We demonstrate that miR-155 induces resistance to multiple chemotherapeutic agents
, and that downregulation of miR-155 successfully resensitizes tumors to chemotherapy
We show that anti-miR-155-DOPC can be considered non-toxic
We further demonstrate that miR-155 and
are linked in a negative feedback mechanism and that a combination of high expression of miR-155 and low expression of
is significantly associated with shorter survival in lung cancer.
Our findings support the existence of an miR-155/TP53 feedback loop, which is involved in resistance to chemotherapy and which can be specifically targeted to overcome drug resistance, an important cause of cancer-related death.
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African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other ...inherent genomic differences that contribute to the survival disparities.
To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes.
Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas.
Breast cancer–free interval, tumor molecular features, and genetic variants.
Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean SD age at diagnosis, 55.66 13.01 years; 98.1% n = 151 female) and 776 white patients of European ancestry (mean SD age at diagnosis, 59.51 13.11 years; 99.0% n = 768 female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 formerly HER2)–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11).
On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.
The Immune Landscape of Cancer Bortone, Dante S.; Eddy, James A.; Liu, Yuexin ...
Immunity (Cambridge, Mass.),
04/2018, Letnik:
48, Številka:
4
Journal Article
Recenzirano
Odprti dostop
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune ...subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.
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•Six identified immune subtypes span cancer tissue types and molecular subtypes•Immune subtypes differ by somatic aberrations, microenvironment, and survival•Multiple control modalities of molecular networks affect tumor-immune interactions•These analyses serve as a resource for exploring immunogenicity across cancer types
Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy.
Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with ...better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.
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•Both D3 and M3-UM divide into molecularly distinct subsets with different outcomes•Poor-prognosis M3-UM are characterized by a global DNA methylation pattern•Poor-prognosis M3-UM subsets have distinct genomic, signaling, and immune profiles•EIF1AX and SRSF2/SF3B1 mutant D3-UM have different genomic/DNA methylation profiles
Robertson et al. analyze 80 uveal melanomas (UM) and divide poor-prognosis monosomy 3 UM into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. Somatic copy number changes and DNA methylation profiles separate better-prognosis disomy 3 UM into low or intermediate risk.
We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational ...load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival “neuronal” subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
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•Multiplatform analysis informs muscle-invasive bladder cancer subtyping•A framework associating distinct subtyping with therapeutic options•High mutational load is driven mainly by APOBEC-mediated mutagenesis•APOBEC-related mutational signature corresponds to a 75% 5-year survival
A multiplatform analysis of 412 muscle-invasive bladder cancer patients provides insights into mutational profiles with prognostic value and establishes a framework associating distinct tumor subtypes with clinical options.
We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse ...alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.
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•Comprehensive molecular profiling of 173 pheochromocytoma and paraganglioma tumors•Single drivers in tumors by germline mutation, somatic mutation, or fusion gene•MAML3 fusion gene and CSDE1 somatic mutation define a Wnt-altered subtype•Prognostic markers of metastatic disease include the MAML3 fusion gene
Fishbein et al. show that neuroendocrine tumors, pheochromocytomas and paragangliomas, have a low genome alteration rate but diverse driver alterations, which coalesce into four molecular subtypes. The Wnt-altered subtype, driven by MAML3 fusions and CSDE1 somatic mutations, correlates with poor clinical outcome.
Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 ...major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.
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•Multiplatform genetic analysis of 206 sarcomas of 6 types shows their diversity•Sarcomas harbor many more copy-number alterations than most other cancer types•Inferred immune microenvironment associates with outcome in multiple sarcoma types•Computed histologic nuclear pleomorphism correlates with aneuploidy estimates
Genetic analysis of soft tissue sarcomas shows that they are characterized predominantly by copy-number changes and offers insights into the immune microenviroment to inform clinical trials of checkpoint inhibitors.
Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 ...carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.
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