<i>HPP1</i>
            : A transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers

Young, Joanne; Biden, Kelli G.; Simms, Lisa A.; Huggard, Phillip; Karamatic, Rozemary; Eyre, Helen J.; Sutherland, Grant R.; Herath, Nirmitha I.; Barker, Melissa; Anderson, Gregory J.; FitzPatrick, David R.; Ramm, Grant A.; Jass, Jeremy R.; Leggett, Barbara A.

doi:10.1073/pnas.98.1.265

Cited by 94 publications

(52 citation statements)

References 40 publications

(29 reference statements)

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“…Nonetheless, comparison with literature data indicates that the prevalence of hypermethylation in colon cancer and SB-AC is nearly equal regarding hMLH1 (31,32), p16 INK4A (17,29,32), APC (31, 32) and HPP1 (16). In contrast, hypermethylation of seems to be less frequent in p14 ARF in SB-AC (9%) than in colon cancer (24-38%) (17,29,32).…”

Section: Discussionmentioning

confidence: 80%

“…13,14 Another group found that hMLH1 hypermethylation is correlated with the hypermethylation of the HPP1 gene in patients with gastric cancer. 15 Silencing of the HPP1 and /or APC gene by promotor methylation has been found in colorectal cancer and its precursors, 16 as well as in carcinomas of the gastric cardia and stomach. 17 In contrast, the prevalence of hypermethylation of tumor suppressor genes in SB-AC is poorly investigated so far.…”

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confidence: 99%

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Hypermethylation of hMLH1, HPP1, p14^ARF, p16^INK4A and APC in primary adenocarcinomas of the small bowel

Brücher

Geddert

Langner

et al. 2006

Intl Journal of Cancer

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Small bowel adenocarcinoma (SB-AC) is a very rare tumor entity. Epigenetic alterations, including hypermethylation of DNA mismatch repair genes and tumor suppressor genes, seem to be important for carcinogenesis in tumors of the gastrointestinal tract, but have not yet been investigated in SB-AC. In the current study, the prevalence of hypermethylation in a panel of genes involved in gastrointestinal carcinogenesis (hMLH1, HPP1, p14 ARF , p16 INK4A , APC) was determined in a series of SB-AC. Paraffin-embedded tumor samples from 56 patients with SB-AC who underwent surgical resection between January 1985 and December 2003 were investigated for hypermethylation by means of methylation-specific real-time PCR, and compared with our findings in a previously investigated series of 50 gastric adenocarcinomas. In comparison with adenocarcinomas of the stomach, SB-AC revealed a significantly higher rate of hypermethylation of HPP1 (86% versus 54%, p 5 0.0003), p16 INK4A (32% versus 10%, p 5 0.0006), and a significantly lower rate of hypermethylation of APC (48% versus 84%, p 5 0.0001). Hypermethylation of hMLH1 and p14 ARF was present in 23% and 9% of SB-AC, respectively. Locally advanced tumor categories (pT3/4) showed a higher rate of hypermethylation of HPP1 (90%) than did early tumor categories (pT1/2 categories, 40%; p 5 0.0036). This was also reflected by the correlation between the HPP1 hypermethylation and high UICC stage (p 5 0.02). No correlation was found between hypermethylation and other clinicopathologic parameters such as age, tumor grade and nodal status. Our findings suggest that hypermethylation of hMLH1, HPP1, p16 INK4A and APC is frequent in primary adenocarcinomas of the small bowel. The differences in the hypermethylation spectrum of small bowel and stomach cancer indicate significant epigenetic differences between these tumors. ' 2006 Wiley-Liss, Inc.Key words: small bowel carcinoma; hypermethylation; methylationspecific real-time PCR; gastric cancer Primary adenocarcinomas of the small bowel (SB-AC) are rare. 1-3 Surgeons and physicians are challenged by this tumor because of its infrequency, unspecific symptoms and typically delayed diagnosis. 1,3-5 Prognostic factors are the residual tumor (R category), tumor stage according to the UICC, lymph node metastasis, lymphatic vessel invasion and vascular invasion. [4][5][6] Mucosal contact time with bile acid solutions seems to be one important factor in the development of adenocarcinoma of the small bowel, 7 implicating bile as a potential carcinogen. Other predisposing conditions are small bowel adenomas, familial adenomatous polyposis, celiac disease, cystic fibrosis, peptic ulcer disease 8 and Crohn's disease. 9 Cases occurring in association with ulcerative colitis and backwash ileitis have also been described. 10 An important epigenetic mechanism for silencing tumor suppressor genes during carcinogenesis is the hypermethylation of CpG islands. 11 In certain cancer types, such as colorectal and endometrial cancers, loss of function of the DNA mis...

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Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

Hypermethylation of hMLH1, HPP1, p14^ARF, p16^INK4A and APC in primary adenocarcinomas of the small bowel

Brücher

Geddert

Langner

et al. 2006

Intl Journal of Cancer

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“…DNA methylation was quantified at five 'type A' genes ESR1, GATA5, HIC1, HPP1 and SFRP1 (Issa et al, 1994;Young et al, 2001;Akiyama et al, 2003;Chen et al, 2004;Suzuki et al, 2004) and 10 'type C' markers MLH1, CDKN2A, MGMT, MINT2, MINT31, CACNA1G, IGF2, RUNX3, NEUROG1 and SOCS1 Issa, 2004;Shen et al, 2005Shen et al, , 2007bWeisenberger et al, 2006). Specific 'type A' genes were selected for their relevance to colorectal neoplasia and for evidence (unpublished data) that each had relatively high methylation within peritumoral 'normal' mucosa.…”

Section: Methodsmentioning

confidence: 99%

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

et al. 2009

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“…It is therefore very likely that HPP1 plays a role in cell proliferation, differentiation and adhesion. 12 Moreover, silencing of the HPP1 gene by promoter methylation has been found in colorectal cancer and its precursors. 12 Since the prevalence of hMLH1 and HPP1 hypermethylation in esophageal and cardiac ADC and their possible association have not been investigated so far, we determined these features in 50 esophageal and 50 cardiac ADCs and compared our results with a series of 50 gastric ADCs.…”

mentioning

confidence: 99%

“…12 Moreover, silencing of the HPP1 gene by promoter methylation has been found in colorectal cancer and its precursors. 12 Since the prevalence of hMLH1 and HPP1 hypermethylation in esophageal and cardiac ADC and their possible association have not been investigated so far, we determined these features in 50 esophageal and 50 cardiac ADCs and compared our results with a series of 50 gastric ADCs. The current study was performed to determine whether there are significant differences in the prevalence of hMLH1 and HPP1 hypermethylation in the 3 tumor types.…”

mentioning

confidence: 99%

Correlation of hMLH1 and HPP1 hypermethylation in gastric, but not in esophageal and cardiac adenocarcinoma

Geddert

Kiel

Iskender

et al. 2004

Intl Journal of Cancer

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1 Using methylation-specific real-time PCR, we determined the prevalence of aberrant methylation in the mismatch repair gene hMLH1 and in the recently described HPP1 gene among 50 esophageal, 50 cardiac and 50 gastric ADCs. Additionally, expression of hMLH1 protein was detected immunohistochemically and correlated with DNA MSI. Hypermethylation of hMLH1 was found in 14% of esophageal, 28% of cardiac and 32% of gastric ADCs, whereas HPP1 hypermethylation was found more frequently in the 3 tumor types (64% vs. 38% vs. 54%). In gastric ADC, HPP1 hypermethylation was found more frequently in tumors with concomitant hMLH1 hypermethylation (81%) than in those without hMLH1 hypermethylation (41%, p ‫؍‬ 0.008). Complete loss of hMLH1 protein expression, which was present in 10 carcinomas (5 cardiac and 5 gastric), was invariably correlated with hMLH1 hypermethylation and MSI. In conclusion, our data indicate that MSI and loss of the mismatch repair protein hMLH1, which is mainly caused by hMLH1 gene hypermethylation, are more prevalent in stomach and cardia carcinogenesis than in that of the esophagus. Moreover, in gastric cancer, hMLH1 hypermethylation is correlated with hypermethylation of the HPP1 ADCs of the esophagus and stomach are characterized by important differences concerning etiologic and clinical background. Chronic gastroesophageal reflux disease and subsequent intestinal metaplasia of the esophagus (Barrett's esophagus), on the one side, and Helicobacter pylori infection with subsequent atrophic gastritis, on the other side, are among the most important risk factors for esophageal or gastric ADC, respectively. 1,2 Moreover, the incidence of esophageal ADC has been rising rapidly over the last 3 decades, whereas the incidence of gastric ADC has been declining. 3 Although traditionally considered a gastric carcinoma, cardiac ADC shares a number of features with esophageal ADC, e.g., profound male predominance, rising incidence and etiologic association with chronic gastroesophageal reflux. 4,5 Hypermethylation of CpG islands represents an important epigenetic mechanism for silencing tumor-suppressor genes during carcinogenesis. 6 For example, loss of function of the DNA mismatch repair gene hMLH1 by hypermethylation of its promoter has been described in different cancer types, such as colorectal and endometrial cancers. 6,7 Lack of hMLH1 protein expression strongly decreases the fidelity of DNA replication and has been correlated with MSI, a surrogate marker for the so-called RER phenotype. 8,9 Thus, hypermethylation of hMLH1 has been detected in about 95% of RER-positive gastric ADCs but in only 5% of RER-negative cases. 8 Shibata et al. 10 found an as yet unexplained association between hypermethylation of hMLH1 and HPP1 in a series of 32 gastric ADCs. Currently, only limited data exist about the structural and functional properties of HPP1. It is thought to encode for a cell membrane receptor. The HPP1 protein shares a high grade of structural homology to regulatory proteins of the CNS (i.e., tomoregulin...

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HPP1 : A transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers

Cited by 94 publications

References 40 publications

Hypermethylation of hMLH1, HPP1, p14^ARF, p16^INK4A and APC in primary adenocarcinomas of the small bowel

Hypermethylation of hMLH1, HPP1, p14^ARF, p16^INK4A and APC in primary adenocarcinomas of the small bowel

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

Correlation of hMLH1 and HPP1 hypermethylation in gastric, but not in esophageal and cardiac adenocarcinoma

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HPP1 : A transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers

Cited by 94 publications

References 40 publications

Hypermethylation of hMLH1, HPP1, p14ARF, p16INK4A and APC in primary adenocarcinomas of the small bowel

Hypermethylation of hMLH1, HPP1, p14ARF, p16INK4A and APC in primary adenocarcinomas of the small bowel

DNA methylation within the normal colorectal mucosa is associated with pathway-specific predisposition to cancer

Correlation of hMLH1 and HPP1 hypermethylation in gastric, but not in esophageal and cardiac adenocarcinoma

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Hypermethylation of hMLH1, HPP1, p14^ARF, p16^INK4A and APC in primary adenocarcinomas of the small bowel

Hypermethylation of hMLH1, HPP1, p14^ARF, p16^INK4A and APC in primary adenocarcinomas of the small bowel