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High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

In this Review, Butterfield and Najjar discuss the rationale for combination strategies in cancer, including combinations of different immunotherapies and combinations of immunotherapies with other types of therapies. Moreover, they examine the evolution of biomarker approaches to guide such therapies.

Efficacy of dendritic cell (DC)-based vaccines remains unsatisfactory. Here the authors analyse the transcriptomic and immune-metabolic profiles of DCs from patients enrolled in a DC vaccine trial in late-stage melanoma, suggesting that the metabolic profile of DC is associated with the immunostimulatory potential of the cancer vaccine.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

Ocampo et al. present several structures and the biochemical characterization of a compact Cas9 nuclease, shedding light on how these enzymes function and evolve.

RNA-guided CRISPR-associated transposases (CAST) are natural systems with broad potential in biotechnology. Here, the authors report compact type V-K CAST discovered from genome-resolved metagenomics and demonstrate targeted integration of a large transgene to a safe-harbor site in the human genome.

In a randomized phase 2 trial, sotigalimab, a CD40 agonist, did not significantly improve overall survival in patients with previously untreated metastatic pancreatic cancer when combined with chemotherapy or with nivolumab and chemotherapy. Multi-omic exploratory analyses provide insights into immunologic features associated with clinical benefit.

To accelerate the development of T cell–based immunotherapies that are effective for more patients with cancer, there is an urgent need to decipher the precise attributes of the ideal therapeutic T cell. In March 2021, the Parker Institute of Cancer Immunotherapy and 10x Genomics partnered to bring together a group of T cell immunotherapy researchers and single-cell-technology innovators for a day’s workshop. Participants evaluated the current cutting edge of knowledge, identified areas for focused technology development, and put forward a call to action to the field. Insights were provided on how to best leverage single-cell technologies and key areas for future development were proposed — with the goal of facilitating a better understanding of T cell research and translation of this research into effective cancer immunotherapies. The key points of discussion that emerged from this workshop are summarized here.

Programmable, RNA-guided nucleases are diverse enzymes that have been repurposed for biotechnological applications. Here, the authors mine an extensive genome-resolved metagenomics database and identified uncharacterized families of RNA-guided, compact nucleases.

Assessing metabolic activity within single cells rather than at a population level has a number of advantages. Here, the authors use a flow and mass cytometry based approach that assess the metabolic differences between populations of human immune stimulatory and tolerogenic dendritic cells.

Analyses of in vivo models, cell lines and patient-derived samples show that apolipoprotein B mRNA-editing catalytic subunit 3B (APOBEC3B) not only restrains lung tumor initiation but also that its upregulation is associated with resistance to targeted therapies. This study highlights the complex and context-dependent role of APOBEC3B in lung cancer.

Multiomic profiling of several cohorts of patients treated with immune checkpoint blockade highlights the presence and potential role of B cells and tertiary lymphoid structures in promoting therapy response.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Turajlic and colleagues assess longitudinal antibody and cellular immune responses against SARS-CoV-2 variants of concern in patients with cancer, following either recovery from SARS-CoV-2 infection or vaccination, in two back-to-back reports from the CAPTURE study.

The Cancer Genome Atlas consortium reports on their genome-wide characterization of somatic alterations in colorectal cancer; in addition to revealing a remarkably consistent pattern of genomic alteration, with 24 genes being significantly mutated, the study identifies new targets for therapeutic intervention and suggests an important role for MYC-directed transcriptional activation and repression.

Turajlic and colleagues assess longitudinal antibody and cellular immune responses against SARS-CoV-2 variants of concern in patients with cancer, following either recovery from SARS-CoV-2 infection or vaccination, in two back-to-back reports from the CAPTURE study.

A combined modelling and tumour analysis approach is used to study the temporal and spatial patterns of subclone evolution in the TRACERx renal study. Studying the tumour shape and spatial features of clonal diversity in early-stage tumours may allow the prediction of tumour progression and patterns of subclone diversification over time.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies.

The Cancer Genome Atlas presents an integrative genome-wide analysis of genetic alterations in 279 head and neck squamous cell carcinomas (HNSCCs), which are classified by human papillomavirus (HPV) status; alterations in EGFR, FGFR, PIK3CA and cyclin-dependent kinases are shown to represent candidate targets for therapeutic intervention in most HNSCCs.

The spatial and physical nature of tumour growth remains unclear. Combining whole-tumour images from clear cell renal cell carcinoma with genomic data, the authors show more aggressive subclonal growth and metastasizing subclones in the tumour centre.

The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.

A rare case of cytokine release syndrome in a patient on anti-PD-1 blockade that was likely related to BNT162b2 vaccination supports prospective monitoring of patients with cancer after COVID-19 vaccine administration.

The Cancer Genome Atlas Research Network reports an integrative analysis of more than 400 samples of clear cell renal cell carcinoma based on genomic, DNA methylation, RNA and proteomic characterisation; frequent mutations were identified in the PI(3)K/AKT pathway, suggesting this pathway might be a potential therapeutic target, among the findings is also a demonstration of metabolic remodelling which correlates with tumour stage and severity.

This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

The Cancer Genome Atlas Network describe their multifaceted analyses of primary breast cancers, shedding light on breast cancer heterogeneity; although only three genes (TP53, PIK3CA and GATA3) are mutated at a frequency greater than 10% across all breast cancers, numerous subtype-associated and novel mutations were identified.

In an inter-laboratory study, the authors compare the accuracy and performance of three optical density calibration protocols (colloidal silica, serial dilution of silica microspheres, and colony-forming unit (CFU) assay). They demonstrate that serial dilution of silica microspheres is the best of these tested protocols, allowing precise and robust calibration that is easily assessed for quality control and can also evaluate the effective linear range of an instrument.

Current clinical practice is organized according to tissue or organ of origin of tumors. Now, The Cancer Genome Atlas (TCGA) Research Network has started to identify genomic and other molecular commonalities among a dozen different types of cancer. Emerging similarities and contrasts will form the basis for targeted therapies of the future and for repurposing existing therapies by molecular rather than histological similarities of the diseases.