Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma.

Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study.

Beta papillomaviruses: From foe to friend in skin cancer immunity.

In this issue of Cancer Cell, Son et al. highlight an unexpected role for skin β-papillomaviruses in the protection against skin carcinogenesis. T cell immunity to skin papillomaviruses blocks the expansion of p53 mutant clones in ultraviolet (UV) radiation-damaged skin, preventing the development of skin cancer.

TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.

Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency.

Oncogenic PIK3CA corrupts growth factor signaling specificity.

Technical limitations have prevented understanding of how growth factor signals are encoded in distinct activity patterns of the phosphoinositide 3-kinase (PI3K)/AKT pathway, and how this is altered by oncogenic pathway mutations. We introduce a kinetic, single-cell framework for precise calculations of PI3K-specific information transfer for different growth factors. This features live-cell imaging of PI3K/AKT activity reporters and multiplexed CyTOF measurements of PI3K/AKT and RAS/ERK signaling markers over time.

A deep learning framework deploying segment anything to detect pan-cancer mitotic figures from haematoxylin and eosin-stained slides.

Mitotic activity is an important feature for grading several cancer types. However, counting mitotic figures (cells in division) is a time-consuming and laborious task prone to inter-observer variation. Inaccurate recognition of MFs can lead to incorrect grading and hence potential suboptimal treatment.

Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer.

The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4).

CD19-targeting chimeric antigen receptor T-cell therapy is safe and effective for intra-cardiac B cell non-Hodgkin lymphoma.

Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is highly effective in B-cell blood cancers, but there is limited data on its safety and efficacy in intra-cardiac lymphoma, due to the potential risks of cardiotoxicity and pseudo-progression.

Discussion: We discuss four high-risk cases that were managed with a multi-disciplinary approach, including baseline cardiac risk assessment and surveillance with multimodal cardiac imaging and serum cardiac biomarkers, elective supportive care in the intensive care unit, and early treatment of cytokine release syndrome.

Conclusion: CAR-T therapy can be effective and safe in the treatment of B-cell blood cancers with intra-cardiac disease.

Minimal residual disease in colorectal cancer. Tumor-informed versus tumor-agnostic approaches: unraveling the optimal strategy.

Background: Circulating tumor DNA (ctDNA) analysis has emerged as a minimally invasive tool for detecting minimal residual disease (MRD) in colorectal cancer (CRC) patients. This enables dynamic risk stratification, earlier recurrence detection, and optimized post-surgical treatment. Two primary methodologies have been developed for ctDNA-based MRD detection: tumor-informed strategies, which identify tumor-specific mutations through initial tissue sequencing to guide ctDNA monitoring, and tumor-agnostic approaches, which utilize predefined panels to detect common cancer-associated genomic or epigenomic alterations directly from plasma without prior tissue analysis.

Characteristics and outcomes in patients with lenalidomide-refractory multiple myeloma treated with 1-3 prior lines of therapy: Analysis of individual patient-level data from daratumumab clinical trials.

Background: The introduction of proteasome inhibitors (PIs) and lenalidomide as treatment for newly diagnosed multiple myeloma (MM) has led to an increased population of lenalidomide-refractory patients. Limited data are available characterizing current treatments and outcomes in this difficult-to-treat population.

Methods: Individual patient-level data were analyzed from the treatment arms of multiple daratumumab studies, including APOLLO, CASTOR, CANDOR, EQUULEUS, ALCYONE, MAIA, GRIFFIN, POLLUX, and CASSIOPEIA.

scTrends: A living review of commercial single-cell and spatial 'omic technologies.

Understanding the rapidly evolving landscape of single-cell and spatial omic technologies is crucial for advancing biomedical research and drug development. We provide a living review of both mature and emerging commercial platforms, highlighting key methodologies and trends shaping the field. This review spans from foundational single-cell technologies such as microfluidics and plate-based methods to newer approaches like combinatorial indexing; on the spatial side, we consider next-generation sequencing and imaging-based spatial transcriptomics.

Entrectinib-Induced Myocarditis and Acute Heart Failure Responding to Steroid Treatment: A Case Report.

A 72-year-old man presented to his general practitioner with worsening dyspnea and was diagnosed with having recurrent -positive stage IIIB NSCLC 8 years after initial diagnosis and radical treatment for early stage disease. He was subsequently started on entrectinib but required hospital admissions for recurrent acute kidney injuries on a background of chronic kidney disease. His entrectinib was withheld on day 20 since his first dose of treatment while he was being investigated.

Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression.

Background: Intratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors.

Methods: We developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms.

Optimizing outcomes and personalizing care with targeted agents in advanced cholangiocarcinoma.

Traditional chemotherapy and immunotherapy-based systemic treatments for locally advanced or metastatic cholangiocarcinoma have been associated with poor clinical outcomes driven partly by molecular heterogeneity promoting early treatment resistance and a higher toxicity profile associated with these regimens. Few patients are eligible for upfront surgical resection and clinical studies have been traditionally difficult to conduct due to the orphan nature of this disease. However, increasing use of genomic profiling in clinical practice have led to active investigations of aberrant albeit promising mechanistic therapeutic targets such as IDH-1, FGFRs, BRAF, HER-2 and NTRK.

Origins and impact of extrachromosomal DNA.

Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.

Plain language summary: an analysis of the safety of futibatinib treatment in people with different types of cancer.

What Is This Summary About?: Researchers combined information from three separate phase 1 and 2 clinical trials, including over 400 people who had one of 33 different cancer types and who all received futibatinib in their clinical trial. This type of study is called a pooled analysis. Futibatinib is taken orally (by mouth) as a tablet and works by reducing the activity of a group of proteins called fibroblast growth factor receptors (FGFRs).