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. 2023 Dec;165(6):1561-1564.e3.
doi: 10.1053/j.gastro.2023.08.039. Epub 2023 Sep 1.

Genetic Defect in Submucosal Gland-Associated Caveolin-3: A New Paradigm in Esophageal Adenocarcinoma Risk

Katherine S Garman  1 , Biswa P D Purkayastha  2 , Joyce A Hogue  1 , Ryan Fecteau  3 ; BETRNet CONSORTIUM; Kishore Guda  11 , Amitabh Chak  12
Collaborators, Affiliations

Genetic Defect in Submucosal Gland-Associated Caveolin-3: A New Paradigm in Esophageal Adenocarcinoma Risk

Katherine S Garman et al. Gastroenterology. 2023 Dec.
No abstract available

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Conflict of interest statement

Conflict of interest disclosure: None of the authors report any conflict of interest with this study.

Figures

Figure 1:
Figure 1:
Panel A: Pedigree NN-0001 - Yellow square in left lower quadrant = BE; Blue right upper quadrant = EAC. Proband is indicated with arrowhead. Age of diagnosis, affected individuals whose exomes were sequenced, and individuals carrying the null CAV3 mutation are indicated. Panel B: Expression of C19* variant in mammalian cells shows greatly attenuated expression of small peptide fragment in left lane compared to wild type CAV3 in left lane. Panel C: Immunohistochemistry (IHC) shows absence of CAV3 in normal human esophagus, BE, and EAC (left column, scale bar = 150 μm). Images in remaining columns demonstrate CK5, p63, and CK7 immunostaining in same tissues. Panel D: An ESMG found in an esophagectomy sample from the affected family member with CAV3 mutant with BE and EAC. Histology (50 μm images) demonstrates an ESMG with ADM and atypia (top – H&E) with absence of myoepithelial cells; lack of CAV3 (middle - IHC); and strong patchy CK7 (bottom - IHC). Panel E: Paired H&E and CAV3 IHC images from uninjured and injured esophagus. Top row - 100 μm image of normal mucinous ESMG from uninjured esophagus; IHC demonstrates CAV3 in myoepithelial cells (see magnified inset) around acini, asterisk indicates arterioles with CAV3 as positive controls. Next three rows are from injured esophagus. Second row - 50 μm image of ESMG with ADM in injured esophagus; note, arrows (H&E, left image and IHC, right image) indicate metaplastic acini surrounded by inflammatory infiltrate, magnified inset shows that CAV3 in metaplastic acinar cells appears both cytoplasmic and membranous. Third row - 50 μm images of proliferating inflamed duct associated with ADM, in magnified inset CAV3 staining appears more intense on luminal border. Bottom row – 50 μm images of post-injury neosquamous esophagus, CAV3 is seen in stratified neosquamous epithelium. Panel F: Porcine esophagus was evaluated to detect CAV3 and aSMA by immunofluorescence in uninjured esophagus. Representative regions within a 1000 μm composite image section are shown to demonstrate ESMGs, ducts, and squamous epithelium. Nuclear staining with DAPI is in blue, CAV3 is in red, and aSMA is in green. Top row – normal uninjured squamous epithelium did not demonstrate CAV3 or aSMA. Second row - in contrast, myoepithelial cells within quiescent ESMGs co-expressed CAV3 and aSMA in the uninjured pig esophagus; cells with yellow color indicated by red arrows demonstrate co-localization of CAV3 and aSMA. Third row - during esophageal wound healing, 7 days following radiofrequency ablative injury, white asterisks indicate CAV3 expressing metaplastic epithelial cells in dilated acini within ESMG under the wound; note inflammatory infiltrate in ESMG. Fourth row – white arrowheads indicate ESMG associated dilated proliferating ducts showing CAV3 expressing cells and again note inflammatory infiltrate surrounding ducts; white arrows indicate CAV3 expressing cells in neosquamous epithelium of the healing wound. Note difference between normal epithelium in top panel and inflamed healing epithelium in bottom panel. Panel G: Diagram representing hypothesis on how disruption of CAV3 leads to a susceptibility to BE. Our loss of function CAV3 variant disrupts normal esophageal homeostasis and leads to aberrant metaplastic repair after chronic injury. One hypothesis is that similar to airway and tracheal healing after injury,, CAV3 expressing myoepithelial cells within ESMG may undergo epithelial transition and migrate to normally heal injured squamous esophagus.
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References

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Supplementary concepts