Biology subjects

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium,

Publications and source records attributed to Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium,.

3 recordsLinked to original sources

bioRxiv2026

Polyclonal and single clonal patient-derived organoid models of Barrett oesophagus and oesophageal adenocarcinoma establish a platform for the analysis of heterogeneity in disease progression and therapy response

SUMMARY/ABSTRACTOesophageal adenocarcinoma (OAC) is a major cause of morbidity and mortality. OAC and its precursor, Barrett oesophagus (BO), are defined by substantial early heterogeneity, complicating prevention and treatment of OAC and remaining poorly recapitulated by current in vitro and animal model systems. We have generated 116 patient- and healthy donor-derived organoids (PDOs) spanning normal oesophagogastric tissue, BO and OAC. These PDOs capture population diversity and recapitulate phenotypic, genomic and transcriptomic features of their respective disease stages. We develop a single cell-derived clonal organoid approach and show that this enables us to capture the heterogeneity and isolate high-risk, subclonal populations that are difficult to discern and maintain in bulk PDO cultures. Using this platform, we demonstrate functional importance of this biobank across the pre-malignant to invasive disease spectrum, including a role for BO in shaping fibroblast phenotype within assembloids, and diverse responses of OAC to chemotherapy, radiotherapy and targeted CDK4/6 inhibition. HIGHLIGHTSO_LIPatient- and healthy donor-derived organoids (PDOs) provide a functional platform of disease progression and heterogeneity across normal gastric, non-dysplastic and dysplastic Barrett oesophagus (BO) and oesophageal adenocarcinoma (OAC). C_LIO_LIWe provide a quantitative phenotypic and molecular framework to assess the provenance and fidelity of each PDO model given the heterogeneity of this disease. C_LIO_LIPDOs recapitulate key features of non-dysplastic and dysplastic BO, as well as invasive OAC. C_LIO_LISingle cell-derived clonal organoids (sc-organoids) isolate and maintain high-risk subclonal populations. C_LIO_LIOAC PDOs mirror known population level variation in response to systemic anti-cancer therapies. C_LI

cancer biology↗

bioRxiv2024

Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of oesophageal cancer

CDKN2A is a tumour suppressor located in chromosome 9p21 and frequently lost in Barretts oesophagus (BO) and oesophageal adenocarcinoma (OAC). How CDKN2A and other 9p21 gene co-deletions affect OAC evolution remains understudied. We explored the effects of 9p21 loss in OACs and cancer progressor and non-progressor BOs with matched genomic, transcriptomic, and clinical data. Despite its cancer driver role, CDKN2A loss in BO prevents OAC initiation by counter-selecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in OAC but not BO through context-dependent effects on cell cycle, oxidative phosphorylation, and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed that IFNE loss reduces immune infiltration in BO but not OAC. Mechanistically, CDKN2A loss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management.

cancer biology↗

bioRxiv2021

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

genomics↗