Publications by authors named "Stefan Dentro"

Aging epithelia are colonized by somatic mutations, which are subjected to selection influenced by intrinsic and extrinsic factors. The lack of suitable culture systems has slowed the study of this and other long-term biological processes. Here, we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia.

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Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe Gain Route Identification and Timing In Cancer (GRITIC), a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors.

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Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors.

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Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. Tumour ecosystems feature diverse immune cell types. Myeloid cells, in particular, are prevalent and have a well-established role in promoting the disease.

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Motivation: Few methods exist for timing individual amplification events in regions of focal amplification. Current methods are also limited in the copy number states that they are able to time. Here we introduce AmplificationTimeR, a method for timing higher level copy number gains and inferring the most parsimonious order of events for regions that have undergone both single gains and whole genome duplication.

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The development of cancer is an evolutionary process involving the sequential acquisition of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues. We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution. Integrating the results revealed the existence of two distinct types of prostate cancer that arise from divergent evolutionary trajectories, designated as the Canonical and Alternative evolutionary disease types.

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NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling.

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Article Synopsis
  • Genome sequencing of cancers shows that tumors often consist of different subclones which grow in complex patterns, but the mechanisms behind this are not well understood.
  • A new workflow was developed that maps the genetic composition of these subclones throughout whole tumours, allowing scientists to analyze their growth patterns and characteristics in detail.
  • Applying this method to breast cancer samples revealed distinct growth patterns and unique features of subclones at various stages of cancer, highlighting the potential of spatial genomics in understanding cancer evolution and its microenvironment.
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Aging normal human oesophagus accumulates TP53 mutant clones. These are the origin of most oesophageal squamous carcinomas, in which biallelic TP53 disruption is almost universal. However, how p53 mutant clones expand and contribute to cancer development is unclear.

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Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood.

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The infinite sites model of molecular evolution posits that every position in the genome is mutated at most once. By restricting the number of possible mutation histories, haplotypes and alleles, it forms a cornerstone of tumor phylogenetic analysis and is often implied when calling, phasing and interpreting variants or studying the mutational landscape as a whole. Here we identify 18,295 biallelic mutations, where the same base is mutated independently on both parental copies, in 559 (21%) bulk sequencing samples from the Pan-Cancer Analysis of Whole Genomes study.

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Article Synopsis
  • Black women in the African diaspora face more aggressive breast cancer and higher death rates compared to white women, highlighting a significant health disparity.* -
  • Research of 97 breast cancers from Nigerian women reveals more genomic instability and unique mutations, including early GATA3 mutations, leading to an earlier diagnosis by about 10.5 years.* -
  • The study emphasizes the importance of including diverse populations in medical research and shows that identifying homologous recombination deficiency in tumors can help tailor effective treatments.*
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Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown.

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Article Synopsis
  • * Analysis of 2,658 whole-genome sequences reveals that 95.1% of samples show distinct subclonal expansions that evolve through branching relationships, highlighting the complexity within tumors.
  • * This study identifies specific patterns of driver mutations and other genetic alterations in different cancer types, offering valuable insight into tumor evolution and a resource for understanding subclonal events across cancers.
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Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high- and low-risk sites. The density of mutations varied by location.

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Article Synopsis
  • - Chromosomal instability in cancer leads to significant changes in chromosome number and structure, allowing for diverse somatic copy number alterations (SCNAs) that drive tumor evolution across various cancer types.
  • - An analysis of over 1,400 tumor samples revealed that 37% showed parallel evolutionary events affecting the same key genes, with most recurrent chromosomal losses happening before the whole-genome doubling event.
  • - Furthermore, certain SCNAs were found frequently in metastatic samples, indicating that chromosomal instability facilitates ongoing genetic changes that aid in the progression and diversity of tumors.
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Article Synopsis
  • During aging, progenitor cells accumulate mutations, leading to a mix of normal and mutant clones in tissues, with significant implications for understanding aging and cancer.* -
  • The study focused on the esophageal epithelium in mice, revealing that several genes like Notch1, Notch2, and Trp53 are positively selected among these mutant clones, similar to patterns seen in humans.* -
  • Clone competition dynamics indicate that the success of mutant cells depends on their interaction with neighboring cells, with clonal competition maintaining balance in normal tissue despite the presence of mutations.*
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All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers.

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Cancer develops through a process of somatic evolution. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer.

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About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types.

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Tumor DNA sequencing data can be interpreted by computational methods that analyze genomic heterogeneity to infer evolutionary dynamics. A growing number of studies have used these approaches to link cancer evolution with clinical progression and response to therapy. Although the inference of tumor phylogenies is rapidly becoming standard practice in cancer genome analyses, standards for evaluating them are lacking.

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Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations.

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Background: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC.

Methods: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy.

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