Aims
Oesophageal adenocarcinoma (
EAC
) tumorigenesis has been linked primarily to loss‐of‐function mutations in tumour suppressor genes. Knowledge of specific oncogenes that drive tumour ...progression, and their relationship to outcomes, is limited. High mobility group
AT
‐hook 2 (
HMGA
2
) has been reported to be amplified in a subset of
EAC
s, but the clinicopathological and prognostic implications of
HMGA
2 expression in
EAC
are unknown.
Methods and results
We performed
HMGA
2 immunohistochemistry and fluorescence
in‐situ
hybridization (
FISH
) in
EAC
to determine its clinicopathological and prognostic significance. Ninety‐one primary
EAC
resections without neoadjuvant treatment were identified and immunohistochemistry for
HMGA
2 was performed. The presence or absence of nuclear staining was evaluated and correlated with predetermined clinicopathological parameters and patient outcomes. A selected subset of tumours was subjected to
FISH
to identify alterations at the
HMGA
2
locus.
HMGA
2 expression was present in 25 of 91 (27.4%) tumours.
HMGA
2‐expressing cells were present in solid, poorly differentiated areas of the tumours at the invasive front, or as single infiltrating cells.
FISH
showed that three to four copies of
HMGA
2 are frequently present in
EAC
irrespective of
HMGA
2 protein expression and that high level
HMGA
2
amplification is a rare event.
HMGA
2 expression was associated with numerous adverse clinicopathological parameters, including higher T‐ and N‐stage, the presence of lymphovascular invasion and with a worse recurrence‐free and overall survival.
Conclusion
Our data suggest that
HMGA
2
is regulated in
EAC
primarily through non‐chromosomal‐level alterations that lead to increased
HMGA
2 expression.
HMGA
2‐positive
EAC
correlates with adverse pathological features and worse patient outcomes.
We have examined the mechanism of normal DNA methyltransferase 1 (DNMT1) degradation as well as its mechanism of dysregulation in cancer. We have previously reported that DNMT1 protein levels were ...elevated and abnormally stabilized because of defective degradation through its N-terminal destruction domain. Here, we report that DNMT1 was abnormally stabilized in several cancer cell lines and that, in cells with normal DNMT1 destruction, depletion of CDC20 or FZR1 (two substrate recognition adaptor components of the anaphase-promoting complex) resulted in stabilization of DNMT1 that was partially dependent on the N-terminal destruction domain, thus implicating this cell cycle regulator in the destruction of DNMT1. MAD2, an inhibitor of CDC20, was shown to stabilize DNMT1 levels, and overexpression of MAD2, a consequence of retinoblastoma (RB) pathway dysregulation, was shown to correlate with impaired G1 phase DNMT1 destruction and RB inactivation by hyperphosphorylation in several normal and cancer cell lines. Furthermore, in a series of 85 cases of human breast cancer, a moderately strong, but highly significant, correlation between MAD2 and DNMT1 immunohistochemical staining was observed, yielding a Spearman rank order correlation coefficient of 0.37 ( P < 0.001). This suggests that RB pathway inactivation, a common dysfunction in cancer cells, may be the underlying cause of DNMT1 dysregulation.
Background & Aims: After esophagojejunostomy, rodents develop reflux esophagitis and a columnar-lined esophagus with features of Barrett’s metaplasia. This rodent columnar-lined esophagus has been ...proposed to develop from cellular reprogramming of progenitor cells, but studies on early columnar-lined esophagus development are lacking. We performed a systematic, histologic, and immunophenotypic analysis of columnar-lined esophagus development in rats after esophagojejunostomy. Methods: At various times after esophagojejunostomy in 52 rats, the esophagus was removed and tissue sections were evaluated for type, location, and length of columnar lining. Molecular characteristics were evaluated by immunohistochemistry and immunofluorescence. Results: At week 2, ulceration was seen in esophageal squamous epithelium, starting distally at the esophagojejunostomy anastomosis. Re-epithelialization of the distal ulcer segment occurred via proliferation and expansion of immature-appearing glands budding directly off jejunal crypts, characteristic of wound healing. The columnar-lined esophagus's immunoprofile was similar to jejunal crypt epithelium, and columnar-lined esophagus length increased significantly from 0.15 mm (±0.1 SEM) at 2 weeks to 5.22 mm (±0.37) at 32 weeks. Neoglands were found within esophageal ulcer beds, and spindle-shaped cells expressing epithelial-mesenchymal transition markers were found at the columnar-lined esophagus's leading edge. Only proliferative squamous epithelium was found at the proximal ulcer border. Conclusions: After esophagojejunostomy in rats, metaplastic columnar-lined esophagus develops via a wound healing process that does not appear to involve cellular reprogramming of progenitor cells. This process involves EMT-associated migration of jejunal cells into the esophagus, where they likely have a competitive advantage over squamous cells in the setting of ongoing gastroesophageal reflux disease. Keywords: Gastroesophageal Reflux, Barrett’s Esophagus, Epithelial-Mesenchymal Transition
Context.--The clinicopathologic and prognostic significance of ARID1A mutation in esophageal adenocarcinoma (EAC) is unknown. Objective.--To determine the morphological correlates and prognostic ...significance of ARID1A-deficient EAC. Design.--One hundred twenty cases of primary EAC were evaluated for a predetermined set of histologic features and immunohistochemistry for ARID1A, p53, and MLH1 performed on EAC, as well as adjacent Barrett esophagus and Barrett esophagus-associated dysplasia, when feasible. Associations between categorical clinico-pathologic variables were analyzed by Fisher exact test, and survival analysis was performed by a Cox proportional hazards analysis. Results.--The study group included 97 men and 23 women (mean age, 66 years). Loss of ARID1A expression was seen in 12 of 120 EACs (10%). ARIDlA-deficient tumors showed a strong correlation with a medullary and mucinous phenotype, and 8 of 12 (67%) had at least one feature reminiscent of high microsatellite instability colon carcinomas (mucinous or medullary differentiation, marked intratumoral or peritumoral lymphoid infiltrate). A mutant p53 pattern was present in 52 of 120 EACs (43%) and showed no correlation with ARID1A deficiency (P > .05). MLH1 loss was present in only 2 of 120 EACs (2%); both of which were also deficient in ARID1A. ARID1A-deficient EACs showed a trend toward increased risk of nodal metastasis but had no effect on overall patient survival. Conclusions.--ARID1A-deficient EACs show a phenotype similar to colon cancer with high microsatellite instability but do not appear to have any prognostic significance. Concurrent MLH1 loss is not seen in most ARID1A-deficient tumors, suggesting that ARID1A may be a primary driver of carcinogenesis in a subset of EACs. (Arch Pathol Lab Med. 2017; 141:970-977; doi: 10.5858/arpa.2016-0318-OA)
Background & Aims After esophagojejunostomy, rodents develop reflux esophagitis and a columnar-lined esophagus with features of Barrett’s metaplasia. This rodent columnar-lined esophagus has been ...proposed to develop from cellular reprogramming of progenitor cells, but studies on early columnar-lined esophagus development are lacking. We performed a systematic, histologic, and immunophenotypic analysis of columnar-lined esophagus development in rats after esophagojejunostomy. Methods At various times after esophagojejunostomy in 52 rats, the esophagus was removed and tissue sections were evaluated for type, location, and length of columnar lining. Molecular characteristics were evaluated by immunohistochemistry and immunofluorescence. Results At week 2, ulceration was seen in esophageal squamous epithelium, starting distally at the esophagojejunostomy anastomosis. Re-epithelialization of the distal ulcer segment occurred via proliferation and expansion of immature-appearing glands budding directly off jejunal crypts, characteristic of wound healing. The columnar-lined esophagus's immunoprofile was similar to jejunal crypt epithelium, and columnar-lined esophagus length increased significantly from 0.15 mm (±0.1 SEM) at 2 weeks to 5.22 mm (±0.37) at 32 weeks. Neoglands were found within esophageal ulcer beds, and spindle-shaped cells expressing epithelial-mesenchymal transition markers were found at the columnar-lined esophagus's leading edge. Only proliferative squamous epithelium was found at the proximal ulcer border. Conclusions After esophagojejunostomy in rats, metaplastic columnar-lined esophagus develops via a wound healing process that does not appear to involve cellular reprogramming of progenitor cells. This process involves EMT-associated migration of jejunal cells into the esophagus, where they likely have a competitive advantage over squamous cells in the setting of ongoing gastroesophageal reflux disease.
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