Chak, A. | Search bioRxiv

bioRxiv2021

Caveolin-3 Null Mutation in Family with Barretts Esophagus and Esophageal Adenocarcinoma

ObjectiveBarretts esophagus and esophageal adenocarcinoma demonstrate familial aggregation. The goal was to identify a segregating genetic variant in an large family and subsequently localize esophageal gene expression. MethodsWhole exome sequencing of genomic DNA from affected members of a large family with Barretts esophagus and esophageal adenocarcinoma was analyzed to identify rare coding variants in genes segregating with disease. Histopathological assessment of archived formalin fixed esophageal human and porcine tissues to localize expression of identified genes in esophagus. ResultsA segregating nonsense mutation in the gene Caveolin-3 (CAV3) was identified. Esophageal CAV3 localized to myoepithelial cells around esophageal submucosal glands. Histologic examination of a formalin fixed paraffin embedded esophagectomy specimen from an individual carrying the CAV3 null mutation revealed submucosal glands demonstrating atypical acinar metaplasia with absence of myoepithelial cells and no CAV3+ cells. ConclusionsSubmucosal glands contribute to healing of injured squamous esophagus. We theorize the truncating nonsense CAV3 mutation disrupts normal squamous healing and the organization of submucosal glands, making affected family members susceptible to the proliferation and development of metaplastic columnar Barretts esophagus.

genetics↗

bioRxiv2021

The EphB2-MYC Axis is a Major Determinant of Barrett's Pathobiology and a Therapeutic Vulnerability in Esophageal Cancer

Esophageal adenocarcinoma (EAC), a highly aggressive cancer with limited therapeutic options, often arises in the backdrop of a molecularly-complex esophageal metaplasia disorder, Barretts Esophagus (BE). Using transcriptomics and systems biology analyses of treatment-naive malignant/pre-malignant biopsy tissues, we found Eph receptor B2 (EphB2) tyrosine kinase signaling to be frequently hyperactivated during early stages of EAC development, and across the BE-EAC continuum. Functional studies revealed EphB2 to be an upstream post-translational regulator of c-MYC activity and as a key molecular dependency in BE/EAC. Single-cell transcriptomics in a porcine esophageal 3D spheroid model showed enhanced EphB2 and MYC activity to be significantly associated with BE-like cell fate. shRNA-based knockdown of EphB2 or small molecule inhibitors of MEK, that modulate MYC protein stability, proved effective in suppressing EAC tumor growth in vivo. These findings point to EphB2-MYC axis as an early promoter of EAC and a novel therapeutic vulnerability in this increasingly-prevalent esophageal malignancy. STATEMENT OF SIGNIFICANCEWe identify EphB2 signaling as a potential master regulator and early promoter of esophageal adenocarcinoma, and the proto-oncogene MYC as a key downstream effector of EphB2 function. Targeting the EphB2-MYC axis could be a promising therapeutic strategy for these often refractory and lethal EAC tumors.

cancer biology↗

bioRxiv2020

Barrett's esophagus is the precursor of all esophageal adenocarcinomas

ObjectiveBarretts esophagus (BE) is a known precursor to esophageal adenocarcinoma (EAC) but current clinical data have not been consolidated to address whether BE is the origin of all incident EAC, which would reinforce evidence for BE screening efforts. We aimed to answer whether all expected prevalent BE, diagnosed and undiagnosed, could account for all incident EACs in the US cancer registry data. DesignWe used a multi-scale computational model of EAC that includes the evolutionary process from normal esophagus through BE in individuals from the US population. The model was previously calibrated to fit SEER cancer incidence curves. Here we also utilized age- and sex-specific US census data for numbers at-risk. The primary outcome for model validation was the expected number of EAC cases for a given calendar year. Secondary outcomes included the comparisons of resulting model-predicted prevalence of BE and BE-to-EAC progression to the observed prevalence and progression rates. ResultsThe model estimated the total number of EAC cases in 2010 was 9,970 (95% CI 9,140 - 11,980), which recapitulates all EAC cases from population data. The model simultaneously predicted 8-9% BE prevalence in high-risk males age 45-55, and 0.1-0.2% non-dysplastic BE-to-EAC annual progression in males, consistent with clinical studies. ConclusionThere are no additional EAC cases that plausibly arise in the US population outside the BE pathway. Effective screening of high-risk patients could capture the majority of population destined for EAC progression and decrease mortality through early detection and curative removal of small (pre)cancers during surveillance. Summary BoxWhat is already known about this subject? O_LIBarretts esophagus (BE) patients have a 40 to 50-fold higher risk of developing esophageal adenocarcinoma (EAC) than the general population yet many remain undiagnosed. C_LIO_LIIdentified BE patients receiving surveillance can have early cancers discovered endoscopically, which decreases the high overall EAC-associated mortality. C_LIO_LICurrently around 90% of patients who develop EAC were never part of a BE surveillance program, and those BE patients on surveillance have a low annual progression rate of 0.1 - 0.3% to develop EAC. C_LI What are the new findings?O_LIBy applying a model that incorporates the evolution from normal cells to BE to EAC in patients, we found that the numbers add up - the expected number of EAC cases in the US population are explained by the published rates of BE described above. C_LIO_LIWe cohesively examined the published estimates to determine that all EAC likely arises from both identified BE and occult, undiagnosed BE in the population. C_LI How might it impact on clinical practice in the foreseeable future?O_LIBased on current best estimates, our findings suggest there is no public health need to seek cases of a non-BE alternative pathway to EAC. C_LIO_LIIncreasing efforts for effective, sensitive screening and surveillance of the true BE population will decrease EAC mortality in the coming years. C_LI

cancer biology↗