Featured
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Article
| Open Access
Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer
In an exploratory preplanned biomarker analysis of the phase 3 PARADIGM trial, a lack of resistance gene alterations in baseline circulating tumor DNA (negative hyperselection) was associated with prolonged overall survival after first-line panitumumab with chemotherapy in patients with RAS wild-type metastatic colorectal cancer.
- Kohei Shitara
- , Kei Muro
- & Takayuki Yoshino
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Brief Communication |
Neoplasia risk in patients with Lynch syndrome treated with immune checkpoint blockade
In a retrospective analysis of patients with Lynch syndrome and primary cancers treated with immune checkpoint inhibitors, 12% developed subsequent malignancies, suggesting that this treatment may not eliminate risk in individuals predisposed to mismatch repair-deficient cancers, and ongoing surveillance is warranted.
- Emily C. Harrold
- , Michael B. Foote
- & Zsofia K. Stadler
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News & Views |
Precise, pragmatic and inclusive: the modern era of oncology clinical trials
Innovative clinical trial designs with a patient-centered mission are crucial to advancing modern cancer care; the adaptive phase 2 umbrella study CTONG1702 provides one model for this new era of trial design.
- Michael J. Grant
- & Sarah B. Goldberg
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Article
| Open Access
Camonsertib in DNA damage response-deficient advanced solid tumors: phase 1 trial results
In patients with DNA damage response-deficient solid tumors, the oral ATR kinase inhibitor camonsertib was well tolerated; a recommended phase 2 dose was identified; and encouraging anti-tumor activity was observed, with the highest response rate observed in patients with ovarian cancer.
- Timothy A. Yap
- , Elisa Fontana
- & Ezra Rosen
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Article
| Open Access
Genetically adjusted PSA levels for prostate cancer screening
Analyses of large population-based cohorts and clinical trials show that using polygenic scores to account for variability in PSA levels improves detection of prostate cancer, suggesting an approach for enhancing screening accuracy.
- Linda Kachuri
- , Thomas J. Hoffmann
- & John S. Witte
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Research Briefing |
Immune–microbiota interactions affect the prognosis of patients with colon cancer
We characterized cancer cells, immune responses and the microbiota composition in a cohort of primary colon cancers. Multi-omic analyses defined parameters associated with favorable prognosis, including a score that captured the intratumoral immune response and a specific microbiome signature. This data repository (atlas and compass of immune–cancer–microbiome interactions (AC-ICAM)) is publicly available.
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Article
| Open Access
Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology
The integration of DNA methylation profiling and targeted sequencing with neuropathology improves the diagnostic accuracy of central nervous system tumors in a population-based cohort of more than 1,200 newly diagnosed pediatric patients.
- Dominik Sturm
- , David Capper
- & David. T. W. Jones
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Article |
Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome
Integrative genomic and transcriptomic analyses reveal molecular events defining Richter transformation from CLL, and highlight the potential of cell-free DNA for early detection.
- Erin M. Parry
- , Ignaty Leshchiner
- & Catherine J. Wu
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Article |
Germline variants associated with toxicity to immune checkpoint blockade
A genome-wide association study in large cohorts of patients with different types of cancer treated with immune checkpoint inhibitors identifies genetic variants associated with immune-related adverse events.
- Stefan Groha
- , Sarah Abou Alaiwi
- & Alexander Gusev
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Research Briefing |
The KRASG12D inhibitor MRTX1133 elucidates KRAS-mediated oncogenesis
The identification of KRASG12C inhibitors has reignited interest in targeting RAS proteins. This work describes the discovery of the KRASG12D-specific inhibitor MRTX1133 and demonstrates the feasibility of potently and selectively targeting this oncogenic variant. MRTX1133 treatment markedly inhibited KRAS-dependent signaling and induced tumor regression in xenograft models harboring the KRASG12D mutation.
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Article
| Open Access
Detection of early seeding of Richter transformation in chronic lymphocytic leukemia
Single-cell genomic and transcriptomic analyses of longitudinal samples of patients with Richter syndrome reveal the presence and dynamics of clones driving transformation from chronic lymphocytic leukemia years before clinical manifestation
- Ferran Nadeu
- , Romina Royo
- & Elías Campo
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Article |
Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer
An interim report from the GAIN/iCat2 study shows that molecular profiling of pediatric solid malignancies clarifies diagnostic classifications and provides opportunities for matched targeted therapy.
- Alanna J. Church
- , Laura B. Corson
- & Katherine A. Janeway
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Brief Communication |
High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster
First responders to the World Trade Center disaster, who were exposed to particulate matter containing potential carcinogens, have a high burden of somatic mutations in blood cells, raising their risk for cancer and other diseases and highlighting the need for enhanced health screening of these individuals.
- Sakshi Jasra
- , Orsi Giricz
- & Amit Verma
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Article
| Open Access
Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.
- Anirban Das
- , Sumedha Sudhaman
- & Uri Tabori
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Article |
Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis
Analysis of single-nucleotide variants and copy number alterations gives a more complete picture of clonal hematopoiesis and its impact on hematological malignancy and cardiovascular disease.
- Ryunosuke Saiki
- , Yukihide Momozawa
- & Seishi Ogawa
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Brief Communication |
Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma
Biallelic loss of BCMA caused a patient with multiple myeloma to relapse after anti-BCMA CAR T cell treatment. Baseline heterozygous BCMA deletions might be a risk factor for this form of resistance.
- Matteo C. Da Vià
- , Oliver Dietrich
- & Leo Rasche
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Article |
Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma
Personalized neoantigen vaccination in patients with melanoma elicits durable and specific memory T cell clones that have cytotoxic gene signatures and can diversify to include nonvaccine neoantigen specificities.
- Zhuting Hu
- , Donna E. Leet
- & Patrick A. Ott
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News & Views |
Liquid biopsy versus tumor biopsy for clinical-trial recruitment
Studies demonstrate the efficacy of screening by liquid biopsy for enrollment in clinical trials of precision cancer therapy.
- Ryan B. Corcoran
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Article |
Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer
The Zero Childhood Cancer pediatric precision medicine program informs treatment recommendations for children with high-risk cancers through comprehensive molecular profiling
- Marie Wong
- , Chelsea Mayoh
- & Mark J. Cowley
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Correspondence |
Support systems to guide clinical decision-making in precision oncology: The Cancer Core Europe Molecular Tumor Board Portal
- David Tamborero
- , Rodrigo Dienstmann
- & Janne Lehtiö
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Brief Communication |
Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes
A cell-free DNA-methylation sequencing assay accurately identifies renal cell carcinoma using plasma and urine samples.
- Pier Vitale Nuzzo
- , Jacob E. Berchuck
- & Matthew L. Freedman
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Letter |
Colibactin DNA-damage signature indicates mutational impact in colorectal cancer
Identification of a DNA-damage signature induced by colibactin, a toxin expressed by some strains of Escherichia coli, is enriched in human colorectal cancers.
- Paulina J. Dziubańska-Kusibab
- , Hilmar Berger
- & Thomas F. Meyer
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Brief Communication |
Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms
Inhibition of CSF-1R with recurrent activating alterations and other actionable targets identified by genomic sequencing elicits clinical activity in patients with histiocytosis.
- Benjamin H. Durham
- , Estibaliz Lopez Rodrigo
- & Omar Abdel-Wahab
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Letter |
Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study
Whole-genome sequencing in triple-negative breast cancer supports the prognostic value of the HRDetect mutational-signature-based algorithm for improving patient stratification in a real-world, population-based clinical diagnostic setting.
- Johan Staaf
- , Dominik Glodzik
- & Serena Nik-Zainal
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Letter |
Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers
Direct prospective comparison of circulating tumor DNA and tissue biopsy sequencing shows the superiority of liquid biopsies for capturing clinically relevant alterations mediating resistance to targeted therapies in cancer patients.
- Aparna R. Parikh
- , Ignaty Leshchiner
- & Ryan B. Corcoran
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Review Article |
Developmental origins and emerging therapeutic opportunities for childhood cancer
Childhood cancers are developmentally distinct from adult cancers and arise from cellular reprogramming as a result of epigenetic mutations or gene fusions, providing unique therapeutic opportunities.
- Mariella Filbin
- & Michelle Monje
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Letter |
Small-molecule targeting of brachyury transcription factor addiction in chordoma
A combination of genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling enables the discovery of therapeutically targetable tumor dependencies in rare tumors.
- Tanaz Sharifnia
- , Mathias J. Wawer
- & Stuart L. Schreiber
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Brief Communication |
Ultraviolet radiation–induced DNA damage is prognostic for outcome in melanoma
Mutational signatures in melanoma are associated with prognostic features in patients and suggest distinct disease etiologies associated with the influence of different wavelengths of ultraviolet radiation.
- Lucas D. Trucco
- , Piyushkumar A. Mundra
- & Richard Marais
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News & Views |
Linking brain tumors and epileptic seizures
Mutationally activated BRAF-V600E influences the behavior of different types of cells in the brain and leads to promotion of seizures as well as brain tumors, indicating how both can be pharmacologically targeted in the clinic.
- Jean M. Mulcahy Levy
- & Martin McMahon
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Article |
Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy
Interactions between the MLL3 histone methyltransferase and the BAP1–UTX complex set the level of histone H3K27 methylation and suggest a new therapy for MLL3-mutant cancer.
- Lu Wang
- , Zibo Zhao
- & Ali Shilatifard
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Article |
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial
The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2-mutated tumors and a greater response to taxanes in the nonbasal subtype.
- Andrew Tutt
- , Holly Tovey
- & Judith M. Bliss
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Article |
Recurrent ECSIT mutation encoding V140A triggers hyperinflammation and promotes hemophagocytic syndrome in extranodal NK/T cell lymphoma
A recurrent ECSIT mutation in individuals with extranodal natural killer/T cell lymphoma induces NFκB in cancer cells, leading to macrophage activation, and associates with progression to fatal hemophagocytic syndrome. NFκB-targeting therapy produced stable remission in two patients.
- Haijun Wen
- , Huajuan Ma
- & Quentin Liu
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Review Article |
Clonal evolution in leukemia
In this Review, Ferrando and López-Otín discuss the role of clonal evolution in leukemia and propose that better understanding of the evolutionary biography of human leukemias and related blood cell malignancies may contribute to improve their clinical management.
- Adolfo A Ferrando
- & Carlos López-Otín
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Letter |
Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas
Inactivating mutations in ACTRT1 or surrounding noncoding sequences transcribed into functional enhancer RNAs cause aberrant activation of Hedgehog signaling in both sporadic and inherited forms, such as Bazex–Dupré–Christol syndrome, of basal cell carcinoma. These findings identify a new tumor-suppressor gene and underscore the functional relevance of genomic alterations in noncoding transcribed regions in tumor development.
- Elodie Bal
- , Hyun-Sook Park
- & Asma Smahi
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Article |
Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors
Different mutations found in endometrial and prostate tumors affecting the substrate-recognition domain of SPOP, a component of the E3 ubiquitin ligase complex, result in opposing degradation activity of BET proteins and response to BET inhibitors. This work, along with findings by Zhang et al. and Dai et al., highlights the divergent effects of recurrent mutations affecting different residues within the same functional domain of SPOP and provides scientific rationale to guide the administration of BET inhibitors in endometrial and prostate cancer patients harboring SPOP mutations.
- Hana Janouskova
- , Geniver El Tekle
- & Jean-Philippe P Theurillat
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News Feature |
Shapeshifters in cancer: How some tumor cells change phenotype to evade therapy
- Amanda B Keener
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Article |
Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia
Genome-wide methylome sequencing of serial samples obtained from patients with acute myeloid leukemia reveals that epigenetic alleles and genetic alleles follow independent courses during disease evolution.
- Sheng Li
- , Francine E Garrett-Bakelman
- & Christopher E Mason
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Article |
An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation
Conditional expression of the most common somatic gain-of-function Ezh2 mutation in mouse models of melanoma and lymphoma reveals insight into its cooperation with other oncogenic events and its effects on the epigenome.
- George P Souroullas
- , William R Jeck
- & Norman E Sharpless
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Technical Report |
Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles
Fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq) enables accurate detection of histone marks on chromatin extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples.
- Paloma Cejas
- , Lewyn Li
- & Henry W Long
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News & Views |
PARP inhibitors: a treatment option for AML?
A new study provides a rationale for the use of poly (ADP-ribose) polymerase (PARP) inhibitors to trigger irreparable DNA damage as a therapeutic approach in acute myeloid leukemia (AML). It also provides support for combining PARP inhibitors with agents that reduce HOXA9 protein levels.
- Lan Wang
- , Pierre-Jacques Hamard
- & Stephen D Nimer
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Resource |
Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers
Understanding tumor metastasis is crucial to developing more effective cancer therapies. Here McCreery et al. analyzed the mutational profile of metastases from chemically induced skin tumors in mice and found that parallel evolution of synchronously disseminated tumor cells underlies most metastasis.
- Melissa Q McCreery
- , Kyle D Halliwill
- & Allan Balmain
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Letter |
Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma
The authors find that alterations in retrotransposition can occur at different stages in the evolution of pancreatic adenocarcinoma.
- Nemanja Rodić
- , Jared P Steranka
- & Kathleen H Burns
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News & Views |
Toward recreating colon cancer in human organoids
Experimental modeling of cancer typically uses in vitro culture of transformed cell lines or in vivo animal models. A new study using CRISPR-Cas9 to engineer oncogenic mutations into three-dimensional human colon organoid cultures yields insights into colorectal cancer tumorigenesis.
- Ameen A Salahudeen
- & Calvin J Kuo
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Letter |
Modeling colorectal cancer using CRISPR-Cas9–mediated engineering of human intestinal organoids
Genome editing applied to human intestinal organoids enables the study of the functional effects of mutations recurrent in human tumors.
- Mami Matano
- , Shoichi Date
- & Toshiro Sato
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Editorial |
The future of cancer genomics
With the completion of The Cancer Genome Atlas, it is time to evaluate its impact and mine its data to gain a better understanding of cancer biology and therapy.
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Letter |
Mutations in G protein β subunits promote transformation and kinase inhibitor resistance
The authors identify mutations in β subunits of G proteins that promote transformation and therapy resistance.
- Akinori Yoda
- , Guillaume Adelmant
- & Andrew A Lane
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Analysis |
Age-related mutations associated with clonal hematopoietic expansion and malignancies
Systematic analysis of cancer-associated mutations in the blood cells of healthy individuals.
- Mingchao Xie
- , Charles Lu
- & Li Ding
Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial
Largest genetic study of breast cancer in African Americans launched
All aboard: Will molecular tumor boards help cancer patients?