Epigenetic Heritability of Cell Plasticity Drives Cancer Drug Resistance through a One-to-Many Genotype-to-Phenotype Paradigm.

Unlabelled: Cancer drug resistance is multifactorial, driven by heritable (epi)genetic changes but also by phenotypic plasticity. In this study, we dissected the drivers of resistance by perturbing organoids derived from patients with colorectal cancer longitudinally with drugs in sequence. Combined longitudinal lineage tracking, single-cell multiomics analysis, evolutionary modeling, and machine learning revealed that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences.

Heterogeneity and evolution of DNA mutation rates in microsatellite stable colorectal cancer.

Historically, DNA sequence mutability has been considered relatively uniform and low in tumors with chromosomal instability (CIN), based on the assumption that high mutability would be detrimental in karyotypically aberrant contexts. Recent in silico analyses have challenged this view, suggesting some heterogeneity in mutation rates across CIN tumors; however, these predictions lack experimental validation. It also remains unclear how the intertumor variability of mutation rates compares to intratumor diversification and evolves along disease progression, whether mutation rates are functionally relevant in CIN cancers, and which mutational processes shape mutational accrual during CIN tumor onset and evolution.

Low-coverage whole genome sequencing of low-grade dysplasia strongly predicts advanced neoplasia risk in ulcerative colitis.

Background: The risk of developing advanced neoplasia (AN; colorectal cancer and/or high-grade dysplasia) in ulcerative colitis (UC) patients with a low-grade dysplasia (LGD) lesion is variable and difficult to predict. This is a major challenge for effective clinical management.

Objective: We aimed to provide accurate AN risk stratification in UC patients with LGD.

Stratified Medicine Pediatrics: Cell-Free DNA and Serial Tumor Sequencing Identifies Subtype-Specific Cancer Evolution and Epigenetic States.

In tumors of childhood, we identify mutations in epigenetic genes as drivers of relapse, with matched cfDNA sequencing showing significant intratumor genetic heterogeneity and cell-state specific patterns of chromatin accessibility. This highlights the power of cfDNA analysis to identify both genetic and epigenetic drivers of aggressive disease in pediatric cancers.

Tumor evolution metrics predict recurrence beyond 10 years in locally advanced prostate cancer.

Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up.

A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations.

Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB).

Long-term Multimodal Recording Reveals Epigenetic Adaptation Routes in Dormant Breast Cancer Cells.

Unlabelled: Patients with estrogen receptor-positive breast cancer receive adjuvant endocrine therapies (ET) that delay relapse by targeting clinically undetectable micrometastatic deposits. Yet, up to 50% of patients relapse even decades after surgery through unknown mechanisms likely involving dormancy. To investigate genetic and transcriptional changes underlying tumor awakening, we analyzed late relapse patients and longitudinally profiled a rare cohort treated with long-term neoadjuvant ETs until progression.

Epigenome and early selection determine the tumour-immune evolutionary trajectory of colorectal cancer.

Immune system control is a major hurdle that cancer evolution must circumvent. The relative timing and evolutionary dynamics of subclones that have escaped immune control remain incompletely characterized, and how immune-mediated selection shapes the epigenome has received little attention. Here, we infer the genome- and epigenome-driven evolutionary dynamics of tumour-immune coevolution within primary colorectal cancers (CRCs).

Phenotypic plasticity and genetic control in colorectal cancer evolution.

Genetic and epigenetic variation, together with transcriptional plasticity, contribute to intratumour heterogeneity. The interplay of these biological processes and their respective contributions to tumour evolution remain unknown. Here we show that intratumour genetic ancestry only infrequently affects gene expression traits and subclonal evolution in colorectal cancer (CRC).

The co-evolution of the genome and epigenome in colorectal cancer.

Colorectal malignancies are a leading cause of cancer-related deathand have undergone extensive genomic study. However, DNA mutations alone do not fully explain malignant transformation. Here we investigate the co-evolution of the genome and epigenome of colorectal tumours at single-clone resolution using spatial multi-omic profiling of individual glands.

EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers.

Objective: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).

Design: CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population.

Subclonal reconstruction of tumors by using machine learning and population genetics.

Most cancer genomic data are generated from bulk samples composed of mixtures of cancer subpopulations, as well as normal cells. Subclonal reconstruction methods based on machine learning aim to separate those subpopulations in a sample and infer their evolutionary history. However, current approaches are entirely data driven and agnostic to evolutionary theory.

Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.

Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance.

Mapping the breast cancer metastatic cascade onto ctDNA using genetic and epigenetic clonal tracking.

Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient's cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown.

Measuring single cell divisions in human tissues from multi-region sequencing data.

Both normal tissue development and cancer growth are driven by a branching process of cell division and mutation accumulation that leads to intra-tissue genetic heterogeneity. However, quantifying somatic evolution in humans remains challenging. Here, we show that multi-sample genomic data from a single time point of normal and cancer tissues contains information on single-cell divisions.

Somatic TP53 Mutations Are Detectable in Circulating Tumor DNA from Children with Anaplastic Wilms Tumors.

Background: Diffuse anaplastic Wilms tumor (DAWT) is a rare, high-risk subtype that is often missed on diagnostic needle biopsy. Somatic mutations in TP53 are associated with the development of anaplasia and with poorer survival, particularly in advanced-stage disease. Early identification of DAWT harboring TP53 abnormalities could improve risk stratification of initial therapy and monitoring for recurrence.

The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer.

The most significant prognostic factor in early breast cancer is lymph node involvement. This stage between localized and systemic disease is key to understanding breast cancer progression; however, our knowledge of the evolution of lymph node malignant invasion remains limited, as most currently available data are derived from primary tumors. In 11 patients with treatment-naïve node-positive early breast cancer without clinical evidence of distant metastasis, we investigated lymph node evolution using spatial multiregion sequencing ( = 78 samples) of primary and lymph node deposits and genomic profiling of matched longitudinal circulating tumor DNA (ctDNA).

Intra-Tumor Genetic Heterogeneity in Wilms Tumor: Clonal Evolution and Clinical Implications.

The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors.