Featured
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Article
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Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology
Deconvolution of cfDNA fragmentation benefits from cell type-specific reference data. Here, the authors create a disease agnostic cfDNA cell type of origin analysis and show it can successfully predict cell types of origin from plasma samples.
- Kate E. Stanley
- , Tatjana Jatsenko
- & Joris Robert Vermeesch
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Article
| Open Access
Enabling large-scale screening of Barrett’s esophagus using weakly supervised deep learning in histopathology
Diagnosis of Barrett’s esophagus depends on pathologist assessment of stained slides. Here, the authors utilise a deep learning approach to prioritize potential cases using diagnostic labels in two datasets, with the aim to improve Barrett’s screening capacity.
- Kenza Bouzid
- , Harshita Sharma
- & Javier Alvarez-Valle
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Article
| Open Access
Metabolomic machine learning predictor for diagnosis and prognosis of gastric cancer
Gastric cancer detection by endoscopy is intrusive and time-consuming, and early detection is key to improving survival. Here, the authors propose a metabolite-based model to enable early detection.
- Yangzi Chen
- , Bohong Wang
- & Zeping Hu
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Article
| Open Access
Causes of death among people living with metastatic cancer
Studying survivorship and causes of death in patients with metastatic cancer remains an important task. Here, the authors characterise the causes of death in over a million patients with metastatic cancer, and predict the risk of death after diagnosis due to cancer-related or other causes.
- Kyle Mani
- , Daxuan Deng
- & Nicholas G. Zaorsky
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Article
| Open Access
Terminal modifications independent cell-free RNA sequencing enables sensitive early cancer detection and classification
Cell free RNA is a potentially valuable resource to detect cancer, however, its low concentration in plasma can limit usefulness. Here, the authors devise a library preparation method from 100ul of plasma, and apply to multiple cancer types to detect and classify cancer patients
- Jun Wang
- , Jinyong Huang
- & Deming Gou
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Article
| Open Access
The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients
Telomere fusions are linked to oncogenesis in multiple cancer types, but their patterns are poorly understood. Here, the authors use whole-genome sequencing data to compare fusion events across cancer types, and identify a novel type of telomere fusion pattern associated with the Alternative Lengthening of Telomeres (ALT) pathway that can be used for liquid biopsy analysis.
- Francesc Muyas
- , Manuel José Gómez Rodriguez
- & Ignacio Flores
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Article
| Open Access
Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
Most genetic studies have been done on European cohorts, which affects the efficacy of polygenic risk scores in non-European populations. Here, the authors demonstrate that a colorectal cancer PRS including Asian and European ancestries has improved performance over the European-centric PRS across racial and ethnic groups.
- Minta Thomas
- , Yu-Ru Su
- & Li Hsu
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Article
| Open Access
Multimodal analysis of cell-free DNA whole-methylome sequencing for cancer detection and localization
cfDNA is a promising tool to detect early cancer, however, it has been limited by detection limits and technological ability. Here, the authors develop a method for simultaneous cfDNA methylation, fragmentation and copy number alteration sequencing and apply to a cohort of healthy and cancer patients.
- Fenglong Bie
- , Zhijie Wang
- & Shugeng Gao
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Article
| Open Access
A multiplex blood-based assay targeting DNA methylation in PBMCs enables early detection of breast cancer
DNA methylation pattern of immune cells can be altered during tumour development. Here, the authors identify 4 DNA methylation markers in peripheral blood mononuclear cells which are predictive of breast cancer across multiple cohorts.
- Tiantian Wang
- , Peilong Li
- & Chuanxin Wang
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Article
| Open Access
Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer
Advanced pancreatic cancer is associated with tissue wasting; however, the timing of tissue loss prior to diagnosis and the potential utility of such loss for earlier pancreatic cancer detection are not well understood. Here the authors show that skeletal muscle loss can be detected on CT imaging 1–2 years before a clinical diagnosis of pancreatic cancer.
- Ana Babic
- , Michael H. Rosenthal
- & Brian M. Wolpin
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Article
| Open Access
Pancreatic cancer is associated with medication changes prior to clinical diagnosis
Pancreatic cancer patients have previously been noted to have a change in medication history prior to diagnosis. Here, the authors utilise two large population cohorts to show associations between recent medication changes and risk of a subsequent pancreatic cancer diagnosis.
- Yin Zhang
- , Qiao-Li Wang
- & Brian M. Wolpin
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Article
| Open Access
Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA
Despite advances in ctDNA cancer detection, early detection remains difficult. Here, the authors utilise whole genome sequencing of 2,125 patient samples to create a model for early cancer and tissue of origin detection.
- Mingyun Bae
- , Gyuhee Kim
- & Jung Kyoon Choi
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Article
| Open Access
Single test-based diagnosis of multiple cancer types using Exosome-SERS-AI for early stage cancers
Early detection of multiple cancers through a single method could be clinically important. Here the authors report the diagnostic performance for early detection for multiple cancers using surface-enhanced Raman spectroscopy (SERS) profiles of exosomes from a single blood test and artificial intelligence in a retrospective study design.
- Hyunku Shin
- , Byeong Hyeon Choi
- & Yeonho Choi
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Article
| Open Access
Estimating diagnostic uncertainty in artificial intelligence assisted pathology using conformal prediction
Artificial intelligence prediction accuracy can be reduced with new data. Here, the authors utilise conformal prediction to reduce incorrect predictions in histopathological analysis of prostate cancer biopsies.
- Henrik Olsson
- , Kimmo Kartasalo
- & Martin Eklund
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Article
| Open Access
Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens
Synthetic lethality can be used to identify potential drug targets in cancer based on simultaneous inactivation of two genes through genetic aberrations and gene silencing. Here, the authors develop a statistical framework to identify synthetic lethal pairs from large scale perturbation screens across multiple cancer types.
- Sumana Srivatsa
- , Hesam Montazeri
- & Niko Beerenwinkel
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Article
| Open Access
Uncertainty-informed deep learning models enable high-confidence predictions for digital histopathology
Safe clinical deployment of deep learning models for digital pathology requires reliable estimates of predictive uncertainty. Here the authors describe an algorithm for quantifying whole-slide image uncertainty, demonstrating their approach with models trained to distinguish lung cancer subtypes.
- James M. Dolezal
- , Andrew Srisuwananukorn
- & Alexander T. Pearson
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Article
| Open Access
Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer
Early cancer detection by cell-free DNA (cfDNA) is challenged by the low amount of tumour DNA in cfDNA, tumour heterogeneity and the small patient cohorts. Here, the authors develop a method, cfMethyl-Seq, for cost-effective methylome profiling of cfDNA and for detecting and locating cancer.
- Mary L. Stackpole
- , Weihua Zeng
- & Xianghong Jasmine Zhou
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Article
| Open Access
Combi-seq for multiplexed transcriptome-based profiling of drug combinations using deterministic barcoding in single-cell droplets
Current screens to assess tumour drug resistance require a large amount of material, normally not available from patients. Here the authors report CombiSeq, a scalable microfluidic workflow to screen hundreds of drug combinations in picoliter-size droplets using transcriptome changes as a readout.
- L. Mathur
- , B. Szalai
- & C. A. Merten
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Matters Arising
| Open AccessLimitations of molecular testing in combination with computerized tomographic for lung cancer screening
- Frederic W. Grannis Jr
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Article
| Open Access
High throughput, label-free isolation of circulating tumor cell clusters in meshed microwells
Metastatic CTC clusters remain relatively unexplored due to the lack of optimized and practical technologies for their detection. Here the authors report Cluster-Wells to isolate CTC clusters in whole blood; they show this allows viable cluster retrieval for further molecular and functional analysis.
- Mert Boya
- , Tevhide Ozkaya-Ahmadov
- & A. Fatih Sarioglu
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Article
| Open Access
Multiplexed nanomaterial-assisted laser desorption/ionization for pan-cancer diagnosis and classification
As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. Here, the authors report a machine learning model using mass spectrometry-based liquid biopsy data for pan-cancer screening and classification.
- Hua Zhang
- , Lin Zhao
- & Xiangfeng Duan
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Article
| Open Access
The DNA methylome of cervical cells can predict the presence of ovarian cancer
Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer.
- James E. Barrett
- , Allison Jones
- & Martin Widschwendter
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Article
| Open Access
Robust whole slide image analysis for cervical cancer screening using deep learning
Computer-assisted diagnosis is key for scaling up cervical cancer screening, but current algorithms perform poorly on whole slide image analysis and generalization. Here, the authors present a WSI classification and top lesion cell recommendation system using deep learning, and achieve comparable results with cytologists.
- Shenghua Cheng
- , Sibo Liu
- & Xiuli Liu
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Article
| Open Access
A comprehensive risk score for effective risk stratification and screening of nasopharyngeal carcinoma
Epstein-Barr virus (EBV) is associated with high risk for nasopharyngeal carcinoma (NPC). Here, the authors develop a comprehensive risk score that combines risk effects of EBV and human genetics for NPC risk stratification.
- Xiang Zhou
- , Su-Mei Cao
- & Miao Xu
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Article
| Open Access
Hybrid AI-assistive diagnostic model permits rapid TBS classification of cervical liquid-based thin-layer cell smears
Technical advancements have significantly improved early diagnosis of cervical cancer, but accurate diagnosis is still difficult due to various practical factors. Here, the authors develop an artificial intelligence assistive diagnostic solution to improve cervical liquid-based thin-layer cell smear diagnosis according to clinical TBS criteria in a large multicenter study.
- Xiaohui Zhu
- , Xiaoming Li
- & Yanqing Ding
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Article
| Open Access
A clinical transcriptome approach to patient stratification and therapy selection in acute myeloid leukemia
Several genomic features have been found for acute myeloid leukaemia (AML) but targeted clinical genetic testing fails to predict prognosis. Here, the authors generate an AML prognostic score from RNA-seq data of patients, which successfully stratifies AML patients and which may provide guidance for therapeutic strategies.
- T. Roderick Docking
- , Jeremy D. K. Parker
- & Aly Karsan
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Article
| Open Access
A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection
Cell-free RNA (cfRNA) is a promising analyte for cancer diagnosis. Here, the authors determine the baseline cell-free transcriptome in the absence of cancer and identify tissue- and subtype-specific cfRNA biomarkers in breast and lung cancer patients.
- Matthew H. Larson
- , Wenying Pan
- & Arash Jamshidi
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Article
| Open Access
Patient-derived xenografts and organoids model therapy response in prostate cancer
To date, patients still succumb to cancer, due to tumors not responding to therapy or ultimately acquiring resistance. Here the authors show that by exploiting patient derived organoids and a treatment-naïve patient derived xenograft, patient therapy can be personalized.
- Sofia Karkampouna
- , Federico La Manna
- & Marianna Kruithof-de Julio
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Matters Arising
| Open AccessResponse to Mistry
- Jingsong Zhang
- , Jessica J. Cunningham
- & Robert A. Gatenby
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Article
| Open Access
Disease risk scores for skin cancers
Predicting who will develop skin cancer is difficult. Here, the authors from 23andMe developed a polygenic risk score for skin cancer based on a questionnaire and genetic data from more than 210,000 individuals and suggest that the score could be used in early screening programmes.
- Pierre Fontanillas
- , Babak Alipanahi
- & Adam Auton
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Article
| Open Access
A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia
Identifying leukaemia stem cells (LSC) and defining how they drive tumourigenesis might aid in the treatment of disease. Here, the authors show that a reporter Musashi 2 can serve as a platform to effectively identify leukemic stem cells and it is used to define Syndecan-1 as a dependency for these aggressive, therapy resistant cells.
- Kyle Spinler
- , Jeevisha Bajaj
- & Tannishtha Reya
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Article
| Open Access
Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring
Extracellular vesicles (EVs) are present in circulation at relatively early stages of disease, providing potential opportunities for early cancer diagnosis. Here, the authors report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific EV purification system for early detection of HCC by performing digital scoring on the purified EVs.
- Na Sun
- , Yi-Te Lee
- & Yazhen Zhu
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Article
| Open Access
An optimal posttreatment surveillance strategy for cancer survivors based on an individualized risk-based approach
Monitoring patients for the recurrence of cancer can be costly and it is important to devise the optimum strategy for a given cancer and population. Here, the authors use nasopharyngeal cancer as a model and show using patient data an optimal follow-up schedule to detect recurrence of the cancer.
- Guan-Qun Zhou
- , Chen-Fei Wu
- & Ying Sun
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Article
| Open Access
Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer
Defects in homologous recombination (HR) are found in some triple negative breast cancers, suggesting they may be sensitive to PARP inhibitors. In this phase II clinical trial of the PARP inhibitor rucaparib, changes in Ki67 levels did not correlate with markers of HR deficiency but HR deficiency was detected in 69% of tumours, indicating that PARP inhibitors may be a useful treatment.
- Neha Chopra
- , Holly Tovey
- & Nicholas C. Turner
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Article
| Open Access
Deep learning radiomics can predict axillary lymph node status in early-stage breast cancer
Breast cancer is frequently diagnosed using ultrasound. Here, the authors show that, in addition to ultrasound, shear wave elastography can be used to diagnose breast cancer and, in conjunction with deep learning and radiomics, can predict whether the disease has spread to axillary lymph nodes.
- Xueyi Zheng
- , Zhao Yao
- & Jianhua Zhou
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Article
| Open Access
Methylation analysis of plasma DNA informs etiologies of Epstein-Barr virus-associated diseases
Epstein-Barr virus (EBV) is associated with different malignant diseases and circulating EBV DNA is a biomarker for nasopharyngeal carcinoma (NPC). Here, the authors report that plasma EBV DNA methylation profiles show disease-associated patterns and can help to distinguish NPC and non-NPC subjects.
- W. K. Jacky Lam
- , Peiyong Jiang
- & Y. M. Dennis Lo
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Article
| Open Access
Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker
DNA methylation is an epigenetic modification that control genetic programs. Here, the authors found that the methylation landscape influences the physicochemical properties of DNA and that it can serve as a universal cancer biomarker, and developed a one-step assay for the detection of cancer DNA.
- Abu Ali Ibn Sina
- , Laura G. Carrascosa
- & Matt Trau
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Article
| Open Access
Integrated extracellular microRNA profiling for ovarian cancer screening
Screening methods for early detection of ovarian cancer is technically difficult. Here, the authors investigated circulating microRNA in human blood serum and developed a model using 10 microRNAs to discern between ovarian cancer and being ovarian tumors, solid tumors, and non-cancer patients.
- Akira Yokoi
- , Juntaro Matsuzaki
- & Takahiro Ochiya
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Article
| Open Access
Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers
Several challenges are involved in direct targeting of mutant p53, while targeting altered fitness of cells with loss of wild type p53 is an alternative approach. Here they identify niclosamide to be selectively toxic to p53 deficient cells through a previously unknown mitochondrial uncoupling mechanism.
- R. Kumar
- , L. Coronel
- & C. F. Cheok
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Article
| Open Access
The VAR2CSA malaria protein efficiently retrieves circulating tumor cells in an EpCAM-independent manner
Isolation of circulating tumor cells (CTCs) allows for non-invasive disease monitoring and characterization. Here the authors describe an alternative CTC isolation method based on the ability of the malaria rVAR2 protein to specifically bind oncofetal chondroitin sulfate, which is expressed by all cancer cells
- Mette Ø. Agerbæk
- , Sara R. Bang-Christensen
- & Ali Salanti
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Article
| Open Access
Metas-Chip precisely identifies presence of micrometastasis in live biopsy samples by label free approach
Detecting metastatic cells in tumor/lymph node samples of breast cancer patients is extremely important for diagnosis. Here the authors develop a microelectronic biochip that detect the presence of invasive/metastatic cells in unprocessed biopsies and performs better than the current gold standards.
- Mohammad Saeid Nikshoar
- , Mohammad Ali Khayamian
- & Mohammad Abdolahad
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Article
| Open Access
Novel peptide probes to assess the tensional state of fibronectin fibers in cancer
The extracellular matrix is under variable strain, but we lack the tools to detect differences in strain. Here the authors develop a probe based on a bacterial fibronectin-binding peptide that binds to relaxed fibronectin fibrils and detects relaxed matrix in cell culture, tissue slices and in vivo.
- Simon Arnoldini
- , Alessandra Moscaroli
- & Viola Vogel
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Article
| Open Access
Whole blood stabilization for the microfluidic isolation and molecular characterization of circulating tumor cells
The current FDA-approved whole blood stabilization method for circulating tumor cell (CTC) isolation suffers from RNA degradation. Here the authors combine hypothermic preservation and antiplatelet strategies to stabilize whole blood up to 72 h without compromising CTC yield and RNA integrity.
- Keith H. K. Wong
- , Shannon N. Tessier
- & Mehmet Toner
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Article
| Open Access
Profiling protein expression in circulating tumour cells using microfluidic western blotting
Circulating tumour cells (CTCs) are rare cells found in the blood of certain cancer patients. Here, the authors develop a cytometry tool that appends a microfluidic western blot to a CTC isolation workflow and apply it to profile a panel of proteins in single CTCs isolated from ER+ breast cancer patients.
- Elly Sinkala
- , Elodie Sollier-Christen
- & Amy E. Herr
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Article
| Open Access
Integrated genetic and pharmacologic interrogation of rare cancers
Identifying therapeutic targets in rare cancers is challenging due to the lack of relevant pre-clinical models. Here, the authors generate a cancer cell line from a paediatric patient with a rare undifferentiated sarcoma and through functional genomics and chemical screens identified CDK4 and XPO1 as potential therapeutic targets in this cancer.
- Andrew L. Hong
- , Yuen-Yi Tseng
- & Jesse S. Boehm
NMR and MS reveal characteristic metabolome atlas and optimize esophageal squamous cell carcinoma early detection