The Cancer Genome Atlas Pan-Cancer analysis project

Nature Genetics, Год журнала: 2013, Номер 45(10), С. 1113 - 1120

Опубликована: Сен. 26, 2013

Current clinical practice is organized according to tissue or organ of origin tumors. Now, The Cancer Genome Atlas (TCGA) Research Network has started identify genomic and other molecular commonalities among a dozen different types cancer. Emerging similarities contrasts will form the basis for targeted therapies future repurposing existing by rather than histological diseases. profiled analyzed large numbers human tumors discover aberrations at DNA, RNA, protein epigenetic levels. resulting rich data provide major opportunity develop an integrated picture commonalities, differences emergent themes across tumor lineages. Pan-Cancer initiative compares first 12 TCGA. Analysis their functional roles teach us how extend effective in one cancer type others with similar profile.

Язык: Английский

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Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

Science, Год журнала: 2015, Номер 348(6230), С. 124 - 128

Опубликована: Март 13, 2015

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response this therapy, we used whole-exome sequencing non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated molecular smoking signature, neoantigen burden, DNA repair pathway mutations; each factor burden. one responder, neoantigen-specific CD8+ responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances reactivity. Our results suggest landscape shapes therapy.

Язык: Английский

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Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies

Science Translational Medicine, Год журнала: 2014, Номер 6(224)

Опубликована: Фев. 19, 2014

The development of noninvasive methods to detect and monitor tumors continues be a major challenge in oncology. We used digital polymerase chain reaction-based technologies evaluate the ability circulating tumor DNA (ctDNA) 640 patients with various cancer types. found that ctDNA was detectable >75% advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, head neck cancers, but less than 50% primary brain, renal, prostate, or thyroid cancers. In localized tumors, detected 73, 57, 48, colorectal cancer, gastroesophageal pancreatic breast adenocarcinoma, respectively. often present without cells, suggesting these two biomarkers are distinct entities. separate panel 206 metastatic we showed sensitivity for detection clinically relevant KRAS gene mutations 87.2% its specificity 99.2%. Finally, assessed whether could provide clues into mechanisms underlying resistance epidermal growth factor receptor blockade 24 who objectively responded therapy subsequently relapsed. Twenty-three (96%) developed one more genes involved mitogen-activated protein kinase pathway. Together, data suggest is broadly applicable, sensitive, specific biomarker can variety clinical research purposes multiple different types cancer.

Язык: Английский

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Mutational landscape and significance across 12 major cancer types

Nature, Год журнала: 2013, Номер 502(7471), С. 333 - 339

Опубликована: Окт. 15, 2013

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data analytical results for point mutations small insertions/deletions from 3,281 tumours 12 tumour types as part TCGA Pan-Cancer effort. We illustrate distributions mutation frequencies, contexts types, establish their links tissues origin, environmental/carcinogen influences, DNA repair defects. Using integrated sets, identified 127 significantly mutated genes well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH Wnt/β-catenin receptor tyrosine kinase signalling pathways, cell cycle control) emerging histone, histone modification, splicing, metabolism proteolysis) cellular processes in cancer. average number these varies types; most have two six, indicating that driver required during oncogenesis is relatively small. Mutations transcriptional factors/regulators show tissue specificity, whereas modifiers are often several cancer types. Clinical association identifies having a significant effect on survival, investigations with respect clonal/subclonal architecture delineate temporal orders tumorigenesis. Taken together, lay groundwork developing new diagnostics individualizing treatment. As effort, indels presented; among findings both established cancer, an indication project, authors more than 3,000 representing Among Additional analyses also impact survival likely order mutational events

Язык: Английский

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Maftools: efficient and comprehensive analysis of somatic variants in cancer

Genome Research, Год журнала: 2018, Номер 28(11), С. 1747 - 1756

Опубликована: Окт. 19, 2018

Numerous large-scale genomic studies of matched tumor-normal samples have established the somatic landscapes most cancer types. However, downstream analysis data from mutations entails a number computational and statistical approaches, requiring usage independent software numerous tools. Here, we describe an R Bioconductor package, Maftools, which offers multitude visualization modules that are commonly used in studies, including driver gene identification, pathway, signature, enrichment, association analyses. Maftools only requires variants Mutation Annotation Format (MAF) is larger alignment files. With implementation well-established methods, facilitates data-driven research comparative to discover novel results publicly available sets. In present study, using three well-annotated cohorts The Cancer Genome Atlas (TCGA), application reproduce known results. More importantly, show can also be uncover findings through integrative analysis.

Язык: Английский

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Super-Enhancers in the Control of Cell Identity and Disease

Cell, Год журнала: 2013, Номер 155(4), С. 934 - 947

Опубликована: Окт. 10, 2013

Язык: Английский

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Discovery and saturation analysis of cancer genes across 21 tumour types

Nature, Год журнала: 2014, Номер 505(7484), С. 495 - 501

Опубликована: Янв. 1, 2014

Язык: Английский

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Tumour heterogeneity and resistance to cancer therapies

Nature Reviews Clinical Oncology, Год журнала: 2017, Номер 15(2), С. 81 - 94

Опубликована: Ноя. 8, 2017

Язык: Английский

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Oncogenic Signaling Pathways in The Cancer Genome Atlas

Cell, Год журнала: 2018, Номер 173(2), С. 321 - 337.e10

Опубликована: Апрель 1, 2018

Highlights•Alteration map of 10 signaling pathways across 9,125 samples from 33 cancer types•Reusable, curated pathway templates that include a catalogue driver genes•57% tumors have at least one potentially actionable alteration in these pathways•Co-occurrence alterations suggests combination therapy opportunitiesSummaryGenetic control cell-cycle progression, apoptosis, and cell growth are common hallmarks cancer, but the extent, mechanisms, co-occurrence differ between individual tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions DNA methylation profiled by The Cancer Genome Atlas (TCGA), we analyzed mechanisms patterns somatic ten canonical pathways: cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 β-catenin/Wnt. We charted detailed landscape types, stratified into 64 subtypes, identified mutual exclusivity. Eighty-nine percent had pathways, 57% targetable currently available drugs. Thirty multiple alterations, indicating opportunities for therapy.Graphical abstract

Язык: Английский

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Emerging Biological Principles of Metastasis

Cell, Год журнала: 2017, Номер 168(4), С. 670 - 691

Опубликована: Фев. 1, 2017

Язык: Английский

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