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Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells., Competing Interests: Competing interests: N.M. and R.B. hold a European patent for determination of B cell fraction in mixed samples (PCT/EP2024/062999). N.M., R.B., T.B.K.W. and C.S. hold a European patent for determination of lymphocyte abundance in mixed samples (PCT/EP2022/070694). N.M. has stock options in and has consulted for Achilles Therapeutics and holds a European patent relating to targeting neoantigens (PCT/EP2016/059401), identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004) and predicting survival rates of patients with cancer (PCT/GB2020/050221). C.S. acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc - collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical and Personalis. He is chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the steering committee chair. He is also co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s scientific advisory board (SAB). He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (SAB member, and chair of clinical advisory group), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) (formerly Roche Innovation Centre – Shanghai, Metabomed (until July 2022)), Relay Therapeutics (SAB member), Saga Diagnostics (SAB member), and the Sarah Cannon Research Institute. C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche-Ventana. C.S. has previously held stock/options in GRAIL, and currently has stock/options Bicycle Therapeutics, Relay Therapeutics, and has stock and is co-founder of Achilles Therapeutics. C.S. declares a patent application for methods to lung cancer (PCT/US2017/028013); targeting neoantigens (PCT/EP2016/059401); identifying patent response to immune checkpoint blockade (PCT/EP2016/071471); methods for lung cancer detection (US20190106751A1); identifying patients who respond to cancer treatment (PCT/GB2018/051912); determining HLA LOH (PCT/GB2018/052004); predicting survival rates of patients with cancer (PCT/GB2020/050221), methods and systems for tumour monitoring (PCT/EP2022/077987), Analysis of HLA alleles transcriptional deregulation (PCT/EP2023/059039). C.S. is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumour recurrence. This patent has been licensed to a commercial entity and under their terms of employment C.S is due a revenue share of any revenue generated from such license(s). The remaining authors declare no competing interests., (© 2025. The Author(s).)

Proliferation is a key hallmark of cancer, but whether it differs between evolutionarily distinct clones co-existing within a tumor is unknown. We introduce the Single-cell Proliferation Rate Inference in Non-homogeneous Tumors through Evolutionary Routes (SPRINTER) algorithm that uses single-cell whole-genome DNA sequencing data to enable accurate identification and clone assignment of S- and G2-phase cells, as assessed by generating accurate ground truth data. Applied to a newly generated longitudinal, primary-metastasis-matched dataset of 14,994 non-small cell lung cancer cells, SPRINTER revealed widespread clone proliferation heterogeneity, orthogonally supported by Ki-67 staining, nuclei imaging and clinical imaging. We further demonstrated that high-proliferation clones have increased metastatic seeding potential, increased circulating tumor DNA shedding and clone-specific altered replication timing in proliferation- or metastasis-related genes associated with expression changes. Applied to previously generated datasets of 61,914 breast and ovarian cancer cells, SPRINTER revealed increased single-cell rates of different genomic variants and enrichment of proliferation-related gene amplifications in high-proliferation clones., Competing Interests: Competing interests: A.M.F. is a co-inventor on a patent application to determine methods and systems for tumor monitoring (PCT/EP2022/077987). D.A.M. reports speaker fees from AstraZeneca and Takeda; consultancy fees from AstraZeneca, Thermo Fisher, Takeda, Amgen, Janssen, MIM Software, Bristol Myers Squibb and Eli Lilly and has received educational support from Takeda and Amgen. S.A. is a founder and shareholder of GenomeTherapeutics and scientific advisor to Sangamo Therapeutics, the Institute of Cancer Research, London, and the New York Genome Center, NY. N.M. has stock options in and has consulted for Achilles Therapeutics; holds a European patent in determining HLA LOH (PCT/GB2018/052004) and is a co-inventor to a patent to identifying responders to cancer treatment (PCT/GB2018/051912). M.J.-H. has received funding from CRUK, the National Institutes of Health (NIH) National Cancer Institute, International Association for the Study of Lung Cancer (IASLC) Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR; has consulted for Astex Pharmaceutical and Achilles Therapeutics; is a member of the Achilles Therapeutics Scientific Advisory Board and Steering Committee and has received speaker honoraria from Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster, Bristol Myers Squibb and Genentech. M.J.-H. is listed as a co-inventor on a European patent application relating to methods to detect lung cancer (PCT/US2017/028013); this patent has been licensed to commercial entities, and, under terms of employment, M.J.-H. is due a share of any revenue generated from such license(s) and is also listed as a co-inventor on the GB priority patent application (GB2400424.4) with title—Treatment and Prevention of Lung Cancer. C.S. acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx—collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical and Personalis. He is the chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the Steering Committee Chair. He is also the co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board (SAB). He receives consultant fees from Achilles Therapeutics (also a SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, the China Innovation Centre of Roche (CICoR), formerly Roche Innovation Centre—Shanghai, Metabomed (until July 2022), Relay Therapeutics SAB member, Saga Diagnostics SAB member and the Sarah Cannon Research Institute. C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche-Ventana. C.S. has previously held stock options in Apogen Biotechnologies and GRAIL; currently has stock options in Epic Bioscience, Bicycle Therapeutics and Relay Therapeutics; and has stock options and is cofounder of Achilles Therapeutics. C.S. declares a patent application for methods to lung cancer (PCT/US2017/028013), targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), methods for lung cancer detection (US20190106751A1), identifying patients who respond to cancer treatment (PCT/GB2018/051912), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), methods and systems for tumor monitoring (PCT/EP2022/077987). C.S. is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumor recurrence. This patent has been licensed to a commercial entity, and, under their terms of employment, C.S. is due a revenue share of any revenue generated from such license(s). The other authors declare no competing interests., (© 2024. The Author(s).)

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy., (© 2023. The Author(s).)

Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.