Cancer Prevention Month

In metastatic urothelial carcinoma, it has not been established whether circulating tumor DNA (ctDNA) can replace archival primary tissue to assess mutations and biomarkers. Here, the authors show high mutation concordance between ctDNA and tumour tissue, with high consistency in serial samples.

Patients with solid cancers have high rates of clonal haematopoiesis associated with increased risk of secondary leukemias. Here, by using peripheral blood sequencing data from patients with solid non-hematologic cancer, the authors profile the landscape of mosaic chromosomal alterations and gene mutations, defining patients at high risk of leukemia progression.

Histopathological images are a rich but incompletely explored data type for studying cancer. Here the authors show that convolutional neural networks can be systematically applied across cancer types, enabling comparisons to reveal shared spatial behaviors.

Osteosarcomas are difficult to treat and have a limited response to immunotherapy. Here, the authors analyse osteosarcomas at the single-cell level, and identify both the transdifferentiation of malignant cells and an array of immune cells that could have implications for metastasis and immunotherapy.

The impact of variant calling algorithms on the analysis of intra-tumour heterogeneity has not been properly quantified. Here the authors measure the variability of 22 pipelines with different variant callers and clustering algorithms for subclonal reconstruction to inform future analyses.

Antibody-drug conjugates targeting high expression receptors can suffer from poor tumour penetration. Here, the authors use unconjugated antibody to improve the penetration of an antibody-dye conjugate in a clinical study, supporting further clinical investigation of the co-administration strategy.

Antigen-specific IL9-secreting CD4 Th9 and CD8 Tc9 cells have been previously characterized for their anti-tumour properties. Here, the authors show that ex vivo polarized Th9/Tc9 human CAR-T cells display increased anti-tumor activity in pre-clinical haematological and solid cancer models compared to conventional IL-2 activated CAR-T cells.

HER2+ breast cancer patients can often develop resistance to trastuzumab and therefore potential combination therapies need to be explored. Here, the authors report the results of a multi-center randomized phase II clinical trial evaluating the pathological and molecular responses associated with trastuzumab and/or lapatinib in combination with chemotherapy in HER2+ breast cancer patients.

MYCN amplification is common in neuroblastomas. Here the authors analyse the MYCN amplicon structure and its epigenetic regulation by integrating short- and longread genomic and epigenomic data and find two classes of MYCN amplicons in neuroblastomas, one driven by local enhancers and the other by hijacking of distal regulatory elements.

Cancer patient classification using predictive biomarkers for anti-cancer drug responses is essential for improving therapeutic outcomes. Here, the authors present a machine-learning framework to identify robust drug biomarkers by taking advantage of network-based analyses using pharmacogenomic data.

Fusion oncogenes (FO) are common in cancers, but specific targeting of these chimeric genes are challenging. Here the authors report a CRISPR/Cas9 strategy that targets two intronic regions to disrupt the FOs in cancer cells and show that this approach reduces tumour growth and prolongs survival in animal models of cancer.

The role of long non-coding RNA (lncRNA) in AKT-driven tumor development is unclear. Here, the authors identify VAL (Vimentin associated lncRNA) to be directly induced by AKT/STAT3 signaling and report a lncRNA-mediated mechanism for active AKT-driven EMT-independent lung adenocarcinoma metastasis.

Understanding the evolutionary trajectory of cancer samples may enable understanding resistance to treatment. Here, the authors used single cell sequencing of a cohort of acute myeloid leukemia tumours and identify features of linear and branching evolution in tumours.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

All-trans retinoic acid - ATRA- is known to remodulate the stroma of pancreatic cancer in mice. Here, the authors carried out a Phase Ib trial in pancreatic patients and show that ATRA in combination with chemotherapy is a safe potential treatment for patients with advanced pancreatic cancer, and demonstrate a stromal modulatory effect.

The circular RNA named ciRS-7 is overexpressed in human cancers, however, its spatial cellular expression patterns have not been explored. Here, the authors show that ciRS-7 is not expressed in colon cancer cells, but abundant in stromal cells within tumours, and that cancer-to-stromal cell ratios contribute to correlations between ciRS-7 and miR-7 target genes.

Mongolia has the highest incidence of—and mortality from—hepatocellular carcinoma (HCC) in the world. Here, the authors examine the genomic and transcriptomic landscape of Mongolian HCC, uncover novel driver mutations, and suggest distinct disease etiologies.

There are currently only a few biomarkers to predict the response of muscle invasive bladder cancer to therapy. Here, the authors analyse 300 tumors using exome and RNA sequencing and find that tumors with a high degree of genomic instability and a non-basal/squamous gene expression subtype are most likely to respond to treatment.

The early detection and accurate histopathological diagnosis of gastric cancer are essential factors that can help increase the chances of successful treatment. Here, the authors report on a digital pathology tool achieving high performance on a real world test dataset and show that the system can aid pathologists in improving diagnostic accuracy.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Here the authors show that stronger immune selection and immune editing in females and younger patients lead to the accumulation of poorly presented driver mutations in tumors. These results may explain why young and female patients are characterized by lower response rates to immune checkpoint blockade therapies.

The tryptophan metabolite kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR). Here, the authors show that AHR targeting in IDO/TDO-expressing tumours counteracts a regulatory T cell/macrophage suppressive axis and synergizes with immune checkpoint blockade to hinder tumour growth.

Aberrant cell cycle machinery and loss of the CDKN2A tumor suppressor locus make CDK4/6 a potential target in pancreatic ductal adenocarcinoma (PDAC). Here, the authors use ratiometrically designed nanoparticles to codeliver the CDK4/6 inhibitor palbociclib and the autophagy inhibitor hydroxychloroquine, and show their synergistic therapeutic effects in mouse model of PDAC.

Targeting genotype-independent abnormalities may overcome therapy resistance in glioblastoma despite intratumoral genomic heterogeneity. Here, the authors show that glioblastoma radiation resistance is promoted by purine metabolism and can be overcome by inhibitors of purine synthesis.

Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.

ER-positive breast cancer patients do not usually respond to immunotherapy. In this phase II clinical trial, the authors report the safety and efficacy of combining vorinostat and pembrolizumab with tamoxifen in ER-positive breast cancers and provide evidence that T-cell exhaustion may serve as a potential signature for the response of this combination therapy.

Genetic variants on chromosome 8q24 are associated with prostate cancer risk in men of African ancestry. Here the authors show that one of these variants, rs72725854 alters the enhancer activity in its region, which upon androgen stimulation, activates multiple oncogenic lncRNAs and c-myc.

Metastatic dissemination contributes to the lethality in pancreatic ductal adenocarcinoma (PDAC). Here, the authors perform RNA-sequencing on patient derived circulating tumor cells (CTCs) and identify three major CTC subgroups, and show the therapeutic potential of targeting LIN28B/let-7 pathway to halt cancer metastasis.

Colonoscopy is the most commonly used tool to screen for colorectal cancer (CRC). Here, the authors develop a deep learning model to perform optical diagnosis of CRC by training on a large data set of white-light colonoscopy images and achieve endoscopist-level performance on three independent datasets.

Preclinical evidence suggests that a fasting mimicking diet (FMD) can make cancer cells more vulnerable to chemotherapy, while protecting normal cells. In this randomized phase II clinical trial of 131 patients with HER2 negative early stage breast cancer, the authors demonstrate that FMD is safe and enhances the effects of neoadjuvant chemotherapy on radiological and pathological tumor response.

Both gain-of-function of mutant p53 (GOF) and loss of wild-type p53 (LOH) are independently associated with cancer. Here, the authors show that LOH promotes GOF tumourigenesis by increasing tumor-initiating ability and metastasis.

Fasting diets are emerging as an approach to delay tumor progression and improve cancer therapies. Here, the authors show that the combination of fasting-mimicking diet with vitamin C decreases tumor development and increases chemotherapy efficacy in KRAS-mutant 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.

Penile squamous cell carcinoma (PSCC) is a cancer that is associated with significant mortality. Here, the authors develop a mouse model of PSCC by co-deletion of Smad4 and Apc in the androgen-responsive penile epithelium, and show synergistic efficacy of checkpoint therapy with cabozantinib or celecoxib in their model.

The cell adhesion molecule E-selectin regulates haematopoietic stem cell self-renewal in the bone marrow vascular niche. Here, the authors show E-selectin adhesion directly induces survival signaling in acute myeloid leukaemia and therapeutic inhibition improves chemotherapy outcomes in mice.

Aberrant chromatin structure is often found in cancer. Here, the authors optimise super-resolution microscopy for pathological tissue and discovered a significant decompaction of chromatin folding in early carcinogenesis prior to tumour formation.

Better tumor models are needed for the neuroendocrine subtype of castration resistant prostate cancer (CRPC-NE). Here, the authors develop patient-derived model from circulating tumor cells of a CRPC-NE patient, and provide insights on the sequential acquisition of driver gene mutations promoting NE transdifferentiation.

The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas.

A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.

A significant proportion of patients develop innate or acquired resistance to immune checkpoint inhibitors. Here, the authors show that resistance to anti-PD-1 blockade is associated with TGF-beta driven major histocompatibility complex I (MHCI) down-regulation and a de-differentiated phenotype in melanoma patients.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Progression from asymptomatic smoldering multiple myeloma (SMM) to symptomatic Multiple Myeloma occurs at different rates in different patients. Here, the authors report fewer NRAS and FAM46C mutations and adverse translocations in SMM compared to MM, while KRAS mutations are associated with a shorter time to progression.