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.

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution.

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue.

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone.

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models.

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor.

Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology.

Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts.

Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study.

The evolution of lung cancer and impact of subclonal selection in TRACERx.

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome.

The evolution of non-small cell lung cancer metastases in TRACERx.

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis.

Antibodies against endogenous retroviruses promote lung cancer immunotherapy.

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma.

Body composition and lung cancer-associated cachexia in TRACERx.

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC.

Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.

Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis.

Lung adenocarcinoma promotion by air pollutants.

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development. Here we propose that environmental particulate matter measuring ≤2.

Using DNA sequencing data to quantify T cell fraction and therapy response.

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations.

Social isolation and group size are associated with divergent gene expression in the brain of ant queens.

Social life and isolation pose a complex suite of challenges to organisms prompting significant changes in neural state. However, plasticity in how brains respond to social challenges remains largely unexplored. The fire ants Solenopsis invicta provide an ideal scenario for examining this.

Acute portal vein thrombosis in mild cholecystitis. A consequence of coronavirus disease 2019 infection?

La infección por el virus SARS-CoV-2 provoca, además de cuadros respiratorios graves, episodios trombóticos en múltiples localizaciones debido a una mala regulación de la respuesta inmune. Presentamos el caso de un paciente con colecistitis incipiente que desarrolló trombosis portal aguda sin ningún otro antecedente salvo haber pasado de forma asintomática una infección por COVID-19. Dado que esta complicación es extremadamente infrecuente en pacientes sin factores predisponentes ni infecciones graves, consideramos que la infección por COVID-19 pudo ser un factor desencadenante de la trombosis portal y debemos de tenerlo en cuenta de cara al manejo y tratamiento de futuros casos similares.

Genomic architecture and evolutionary antagonism drive allelic expression bias in the social supergene of red fire ants.

Supergene regions maintain alleles of multiple genes in tight linkage through suppressed recombination. Despite their importance in determining complex phenotypes, our empirical understanding of early supergene evolution is limited. Here we focus on the young 'social' supergene of fire ants, a powerful system for disentangling the effects of evolutionary antagonism and suppressed recombination.

Genes and genomic processes underpinning the social lives of ants.

The >15000 ant species are all highly social and show great variation in colony organization, complexity and behavior. The mechanisms by which such sociality evolved, as well as those underpinning the elaboration of ant societies since their ∼140 million year old common ancestor, have long been pondered. Here, we review recent insights generated using various genomic approaches.

Selective harvest focused on sexual signal traits can lead to extinction under directional environmental change.

Humans commonly harvest animals based on their expression of secondary sexual traits such as horns or antlers. This selective harvest is thought to have little effect on harvested populations because offtake rates are low and usually only the males are targeted. These arguments do not, however, take the relationship between secondary sexual trait expression and animal condition into account: there is increasing evidence that in many cases the degree of expression of such traits is correlated with an animal's overall well-being, which is partly determined by their genetic match to the environment.

Fire ant social chromosomes: Differences in number, sequence and expression of odorant binding proteins.

Variation in social behavior is common yet our knowledge of the mechanisms underpinning its evolution is limited. The fire ant provides a textbook example of a Mendelian element controlling social organization: alternate alleles of a genetic element first identified as encoding an odorant binding protein (OBP) named determine whether a colony accepts one or multiple queens. The potential roles of such a protein in perceiving olfactory cues and evidence of positive selection on its amino acid sequence made it an appealing candidate gene.

Failure of fragmented parathyroid gland autotransplantation to prevent permanent hypoparathyroidism after total thyroidectomy.

Purpose: Parathyroid autotransplantation during total thyroidectomy leads to higher rates of postoperative hypocalcaemia. It has been argued, however, that it prevents permanent hypoparathyroidism. The impact of autografted normal parathyroid gland fragments on long-term parathyroid status has not been assessed properly.

Sexual selection can both increase and decrease extinction probability: reconciling demographic and evolutionary factors.

Previous theoretical models of the effect of sexual selection on average individual fitness in a population have mostly predicted that sexually selected populations should adapt faster and clear deleterious mutations more quickly than populations where sexual selection is not operating. While some laboratory studies have supported these predictions, others have not and studies of field systems have tended to find negative effects of sexual selection, or no effect. The negative effects of sexual selection found in field and other studies are usually ascribed to the costs associated with strong sexual selection acting on the population.