Predictors of Progression to High-Grade Dysplasia or Adenocarcinoma in Barrett’s Esophagus

Whitson, Matthew J.; Falk, Gary W.

doi:10.1016/j.gtc.2015.02.005

Cited by 20 publications

(3 citation statements)

References 102 publications

(119 reference statements)

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“…These timescales of cancer evolution are further supported by the fact that progression of most known precancerous lesions to carcinomas usually spans many years, if not decades [40][41][42][43][44][45] . Our data corroborate these timescales and extend them to cancer types without detectable premalignant conditions, raising the hope that these tumours could also be detected in less malignant stages.…”

Section: Chronological Time Estimatesmentioning

confidence: 95%

The evolutionary history of 2,658 cancers

Gerstung

Jolly

Leshchiner

et al. 2020

Nature

733

541

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Cancer develops through a process of somatic evolution 1,2. 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 3. 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) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection. Similar to the evolution in species, the approximately 10 14 cells in the human body are subject to the forces of mutation and selection 1. This process of somatic evolution begins in the zygote and only comes to rest at death, as cells are constantly exposed to mutagenic stresses, introducing 1-10 mutations per cell division 2. These mutagenic forces lead to a gradual accumulation of point mutations throughout life, observed in a range of healthy tissues 5-11 and cancers 12. Although these mutations are predominantly selectively neutral passenger mutations, some are proliferatively advantageous driver mutations 13. The types of mutation in cancer genomes are well studied, but little is known about the times when these lesions arise during somatic evolution and where the boundary between normal evolution and cancer progression should be drawn. Sequencing of bulk tumour samples enables partial reconstruction of the evolutionary history of individual tumours, based on the catalogue of somatic mutations they have accumulated 3,14,15. These inferences include timing of chromosomal gains during early somatic evolution 16 , phylogenetic analysis of late cancer evolution using matched primary and metastatic tumour samples from individual patients 17-20 , and temporal ordering of driver mutations across many samples 21,22 .

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Section: Chronological Time Estimatesmentioning

confidence: 95%

The evolutionary history of 2,658 cancers

Gerstung

Jolly

Leshchiner

et al. 2020

Nature

733

541

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“…Despite harboring extensive genomic insults, the evolved TP53 deficient gastric organoids lacked morphologic changes as has similarly been noted in human tissues, suggesting that these models not only provide a window into pre-neoplasia but mirror the latency of tumor initiation (12,62). Indeed, the long interval between intestinal metaplasia and GC presents opportunities for earlier intervention and improved risk stratification but necessitates an understanding of the molecular determinants that underpin progression (63).…”

Section: Discussionmentioning

confidence: 97%

Deterministic evolution and stringent selection during pre-neoplasia

Karlsson

Przybilla

et al. 2022

Preprint

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The earliest events during human tumor initiation are poorly characterized but may hold clues as to how to detect and prevent malignancy. Here we model this occult process by engineering TP53 deficiency in primary human gastric organoids and performing experimental evolution in multiple clonally derived cultures over two years, thereby defining causal relationships between this common initiating genetic lesion and resulting phenotypes. TP53 loss elicited progressive aneuploidy, including copy number alterations and complex structural variants that are common in gastric cancers and which follow preferred temporal orders. Longitudinal single cell sequencing of TP53 deficient gastric organoids similarly indicates progression towards malignant transcriptional programs. Moreover, lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programs repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a striking degree of phenotypic convergence in pre-malignant epithelial organoids, implying that the earliest stages of tumorigenesis may be predictable while illuminating evolutionary constraints and barriers to malignant transformation.

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“…There is also significant variability in the surveillance and treatment recommendations by physicians in the management of BE ( 11 , 12 ). Increasing age, segment length, and male sex all have predictive value, and the latest guidelines from the American College of Gastroenterology recommend the use of segment length to guide surveillance intervals for patients with nondysplastic BE (NDBE) ( 1 , 13 ). However, in practice, these variables have limited value because patients with clinically low-risk features such as NDBE, short-segment BE, or female sex can present with prevalent high-grade dysplasia (HGD)/EAC or progress to HGD/EAC during their surveillance interval.…”

Section: Introductionmentioning

confidence: 99%

A Tissue Systems Pathology Test Outperforms the Standard-of-Care Variables in Predicting Progression in Patients With Barrett's Esophagus

Davison,

Goldblum,

Duits

et al. 2023

Clinical and Translational Gastroenterology

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Background: Objective risk stratification is needed for patients with Barrett’s esophagus (BE) to enable risk-aligned management to improve health outcomes. This study evaluated the predictive performance of a tissue systems pathology test (TissueCypher, TSP-9) versus current clinicopathologic variables in a multi-center cohort of BE patients. Methods: Data from 699 BE patients from five published studies on the TSP-9 test was evaluated. 509 patients did not progress during surveillance, 40 were diagnosed with HGD/EAC within 12 months, and 150 progressed to HGD/EAC after 12 months. Age, sex, segment length, hiatal hernia, original and expert pathology review diagnoses, and TSP-9 risk classes were collected. The predictive performance of clinicopathologic variables and TSP-9 was compared, and TSP-9 was evaluated in clinically relevant patient subsets. Results: The sensitivity of the TSP-9 test in detecting progressors was 62.3% compared to 28.3% for expert-confirmed LGD, while the original diagnosis abstracted from medical records did not provide any significant risk stratification. The TSP-9 test identified 57% of progressors with NDBE (P<0.0001). NDBE patients who scored TSP-9 high risk progressed at a similar rate (3.2%/year) to patients with expert-confirmed LGD (3.7%/year). The TSP-9 test provided significant risk stratification in clinically low-risk patients (NDBE, female, short-segment) and clinically high-risk patients (IND/LGD, male, long-segment) (p<0.0001 for comparison of high- vs. low-risk classes). Conclusions: The TSP-9 test predicts risk of progression to HGD/EAC independently of current clinicopathologic variables in BE patients. The test provides objective risk stratification results that may guide management decisions to improve health outcomes for BE patients.

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Predictors of Progression to High-Grade Dysplasia or Adenocarcinoma in Barrett’s Esophagus

Cited by 20 publications

References 102 publications

The evolutionary history of 2,658 cancers

The evolutionary history of 2,658 cancers

Deterministic evolution and stringent selection during pre-neoplasia

A Tissue Systems Pathology Test Outperforms the Standard-of-Care Variables in Predicting Progression in Patients With Barrett's Esophagus

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