paywalled: Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study : The Lancet Oncology

Methods
"Resections done for small and large bowel cancer between January, 2002, and January, 2011, were retrieved. We systematically analysed non-tumorous mucosa from carriers of a Lynch syndrome mutation (set 1: ten patients) and control patients without Lynch syndrome (set 1: nine patients) for MMR protein expression (MLH1, MSH2, and EPCAM) with immunohistochemistry.....

The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors : Modern Pathology

The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors

Abstract

Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. 

To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. 

In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. 

Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage.

abstract: Microparticles From Ovarian Carcinomas Are Shed Into Ascites and Promote Cell Migration (EpCAM/assay/benign ascites/small study)

Abstract

Objective: Microparticles are cellular-derived vesicles (0.5-1.0 [mu]m) composed of cell membrane components, which are actively shed from the surface of various cells, including epithelial cells. We compared microparticles in ascites between women with ovarian carcinoma and women with benign ovarian pathology, and isolated tumor-derived (epithelial cell adhesion molecule [EpCAM]-positive) microparticles for functional analysis and proteomics.

Results: Microparticles in benign pelvic fluid were similar to early and advanced-stage ascites (2.4 vs 2.8 vs 2.0 x 106 microparticles/mL). Advanced stage had a greater proportion of EpCAM-positive microparticles than early or benign disease (13.3% vs 2.5% vs 2.1%; P = 0.001), and serous histology had more than endometrioid (13.2% vs 1.8%; P = 0.01).......
Conclusions: Ascites from advanced-stage and serous ovarian carcinomas contain large numbers of tumor-derived microparticles. In vitro, these microparticles bind to cancer cells and stimulate migration. Tumor-derived microparticles in ascites could mediate the predilection for peritoneal spread in serous ovarian carcinomas.

abstract: Frequency of Rearrangements in Lynch Syndrome Cases Associated with MSH2: Characterization of a New Deletion Involving both EPCAM and the 5′ Part of MSH2

".......The tumors of the carriers show high-level MSI and MSH2 protein loss. The clinical correlation provided evidence that the type of mutation and the extension of the deletions involving the MSH2 gene could have different implications in cancer predisposition. Thus, the identification of EPCAM-MSH2 rearrangements and their comprehensive characterization should be included in the routine mutation screening protocols for Lynch syndrome."

EpCAM expression in primary tumour tissues and metastases: an immunohistochemical analysis - Journal of Clinical Pathology

EpCAM expression in primary tumour tissues and metastases: an immunohistochemical analysis

"....Tumour tissues, such as primary and metastatic breast cancer, frequently overexpress EpCAM.2 Gastl and colleagues observed EpCAM overexpression in 35.6% of patients with invasive breast cancer, and this was associated with poor disease-free and overall survival.3 Moreover, our group has shown that survival decreases significantly with increasing amounts of EpCAM expression.4 EpCAM can be used as prognostic marker in node-positive and node-negative breast cancer.5 Furthermore, frequent and high-level EpCAM expression has been found in adenocarcinomas of the colon, stomach, pancreas and prostate.6 Most soft-tissue tumours and all lymphomas are EpCAM negative. EpCAM overexpression has been associated with a dismal prognosis in other tumour entities, such as gallbladder cancer,7 ovarian cancer8 and pancreatic cancer.9"

See also 
Table 3

EpCAM expression in genitourinary tract cancers (eg: ovarian, clear cell, mucinous...)

Conclusion
EpCAM expression was detected on adenocarcinomas of various primary sites. If EpCAM-specific antibodies are intended to be used in patients with cancer, we recommend prior immunohistochemical evaluation of EpCAM expression, particularly in patients with renal cell cancer, hepatocellular carcinoma, urothelial carcinoma, breast cancer and squamous cell carcinomas.

Apr 2011 Gastroenterology & Endoscopy News - Henry Lynch, MD, Delivers Keynote Address on Lynch Syndrome & Gary H. Hoffman, MD

Note: requires registration (free) to view, discusses sporadic cancer/s, BRAF mutation plus EPCAM mutations, treatment responses etc:

"EPCAM mutation carriers may have phenotypic features that differ from carriers of MSH2 mutations, namely, an almost exclusive expression of site-specific CRC and an absence of extracolonic cancers. “This is really new, and more information is needed on this,” he said".
"Of therapeutic interest, patients with MSI-high tumors may respond differently to chemotherapy."

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"Henry Lynch, MD, Delivers Keynote Address on Lynch Syndrome

Doctor Who First Described the Syndrome Offers Guidance on Management of Inherited CRC

by Caroline Helwick

San Francisco—Microsatellite instability (MSI) is an important factor in the evaluation of Lynch syndrome colorectal cancer (CRC) and should be part of the workup of these patients, according to Henry Lynch, MD, who defined the syndrome and gave the keynote lecture at the 2011 American Society of Clinical Oncology Gastrointestinal Cancers Symposium....."

High-grade, chemotherapy-resistant ovarian carcinomas overexpress epithelial cell adhesion molecule (EpCAM) and are highly sensitive to immunotherapy (RNA/IL-2/Adecatumumab)

Abstract

OBJECTIVE: We evaluated the expression of epithelial cell adhesion molecule (EpCAM) and the potential of MT201 (adecatumumab), a human-monoclonal-antibody that targets EpCAM against chemotherapy-resistant ovarian disease.
STUDY DESIGN: EpCAM expression was evaluated by real-time polymerase chain reaction and flow cytometry. Sensitivity to MT201 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in 4-hour chromium-release assays. The effect of interleukin-2 on MT201 ADCC was also studied.
RESULTS: High messenger RNA expression by real-time polymerase chain reaction and high EpCAM surface expression by flow cytometry was detected in 71% of ovarian cancers (5 of 7 cell lines). Although these cell lines were highly resistant to complement-dependent cytotoxicity and natural killer-dependent cytotoxicity in vitro (range of killing, 0-7%), EpCAM-positive cell lines showed high sensitivity to MT201 ADCC (range of killing, 27-66%). Incubation with interleukin-2 further increased the cytotoxic activity against EpCAM-positive ovarian cancer cell lines.
CONCLUSION: MT201 may represent a novel, potentially highly effective treatment option for patients with ovarian carcinoma whose body is harboring disease refractory to chemotherapy.

abstract: Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study : The Lancet Oncology (multi-national study)

Note: (abstract) study includes 194 mutation carriers with references to pancreatic and duodenal cancers; more information on EPCAM genetics can be found by searching this blog

Duodenal cancer - Wikipedia Duodenal cancer is a cancer in the beginning section of the small intestine. It is relatively rare compared to gastric cancer and colorectal cancer. en.wikipedia.org/wiki/Duodenal_cancer

Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study : The Lancet Oncology

Interpretation

EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

abstract: (Lynch Syndrome) Analysis of EPCAM Protein Expression in Diagnostics of Lynch Syndrome ( -/+ MSH2)

Conclusions: EpCAM is highly expressed in primary chemotherapy- resistant ovarian carcinoma cell lines, and these chemotherapy-resistant tumors are highly sensitive to MT201-mediated cytotoxicity in vitro. MT201 may represent a novel, potentially highly effective treatment option for patients harboring chemotherapy-resistant ovarian carcinoma.

Note: EpCAM epithelial cell adhesion molecule (EpCAM); EpCAM gene can be tested either independently or as part of genetic testing - depending on the testing procedure (eg. Lynch Syndrome); study included clear cell ovarian cancer

EpCAM As a Target in Cancer Therapy -- Journal of Clinical Oncology

Function:  (ref source WIKI)  EpCAM is a pan-epithelial antigen that is expressed on almost all carcinomas. Its constitutional function is being elucidated.

Note: search blog for other references to EpCAM  and in particular to Lynch Syndrome

"...Like for every targeted therapy, the level of EpCAM target expression will have an impact on the outcome of a trial. This was evident for the human anti-EpCAM antibody adecatumumab in patients with metastatic breast cancer. Although a high level and frequency of EpCAM expression can be assumed for patients with colorectal cancer, none of the previous trials prospectively or retrospectively analyzed patients for levels of EpCAM expression on tumor tissue. Particularly for a low-affinity antibody, such as edrecolomab, it may be of importance that tumor cells express EpCAM at a high and not just at an intermediate level..... Future studies will certainly benefit from stratifying patients for their level of EpCAM target expression."

EpCAM-autoantibody levels in the course of disease of ovarian cancer patients.

Med Oncol. 2010 Apr 10
EpCAM-autoantibody levels in the course of disease of ovarian cancer patients.

Heubner M, Errico D, Kasimir-Bauer S, Herlyn D, Kimmig R, Wimberger P.
Clinic of Obstetrics and Gynaecology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany, Martin.heubner@uk-essen.de.

Abstract

EpCAM is a tumor-associated antigen, which is frequently expressed in ovarian cancer.