Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome

Worthley, Daniel L.; Phillips, Kerry; Wayte, Nicci; Schrader, Kasmintan A.; Healey, Sue; Kaurah, Pardeep; Shulkes, Arthur; Grimpen, Florian; Clouston, Andrew D.; Moore, David; Cullen, Digby J.; Ormonde, Donald; Mounkley, D.; Wen, Xin; Lindor, Noralane M.; Carneiro, Fátima; Huntsman, David G.; Chenevix-Trench, Georgia; Suthers, Graeme

doi:10.1136/gutjnl-2011-300348

Cited by 255 publications

(201 citation statements)

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“…In 2012, a new hereditary gastric cancer syndrome was identified, and was coined GAPPS (Gastric Adenocarcinoma and Proximal Polyposis of the Stomach), which is an autosomal dominant condition characterised by fundic gland polyposis with increased risk of developing intestinal type GC and so far unknown genetic cause [9,10].…”

Section: Introductionmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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Familial clustering is seen in 10% of gastric cancer cases and approximately 1-3% of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). In families with HDGC, gastric cancer presents at young age. HDGC is predominantly caused by germline mutations in CDH1 and in a minority by mutations in other genes, including CTNNA1. Early stage HDGC is characterized by a few, up to dozens of intramucosal foci of signet ring cell carcinoma and its precursor lesions. These include in situ signet ring cell carcinoma and pagetoid spread of signet ring cells. Advanced HDGC presents as poorly cohesive/diffuse type carcinoma, normally with very few typical signet ring cells, and has a poor prognosis.Currently, it is unknown which factors drive the progression towards aggressive disease, but it is clear that most intramucosal lesions will not have such progression.Immunohistochemical profile of early and advanced HDGC is often characterised by abnormal E-cadherin immunoexpression, including absent or reduced membranous expression, as well as "dotted" or cytoplasmic expression. However, membranous expression of E-cadherin does not exclude HDGC. Intramucosal HDGC (pT1a) presents with an "indolent" phenotype, characterized by typical signet ring cells without immunoexpression of Ki-67 and p53, while advanced carcinomas (pT>1) display an "aggressive" phenotype with pleomorphic cells, that are immunoreactive for Ki-67 and p53. These features show that the IHC profile is different between intramucosal and more advanced HDGC, providing evidence of phenotypic heterogeneity, and may help to define predictive biomarkers of progression from indolent to aggressive, widely invasive carcinomas.6

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Section: Introductionmentioning

confidence: 99%

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Post

Gullo

Oliveira

et al. 2016

Advances in Experimental Medicine and Biology

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“…The role of spasmolytic polypeptide-expressing metaplasia (SPEM) in the pathogenesis of the lesions with gastric immunophenotype remains to be elucidated. Other evidence stems from hereditary gastric cancer models [hereditary diffuse gastric cancer and gastric adenocarcinoma and proximal polyposis of the stomach (HDGC and GAPPS)] in which GC, diffuse/poorly cohesive type, and intestinal/tubular type, respectively, originate in nonmetaplastic gastric epithelium (fundic gland polyps in the case of GAPPS) [18,19]. Our study provides additional evidence in favor of de novo neoplastic transformation from native gastric mucosa (37.9 % of the dysplastic lesions displayed ''pure'' gastric immunophenotype).…”

Section: Discussionmentioning

confidence: 99%

Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness

et al. 2014

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Background Gastric dysplasia is classified as adenomatous/type I (intestinal phenotype) and foveolar or pyloric/ type II (gastric phenotype) according to morphological (architectural and cytological) features. The immunophenotypic classification of dysplasia, based on the expression of the mucins, CD10 and CDX2, recognizes the following immunophenotypes: intestinal (MUC2, CD10, and CDX2); gastric (MUC5AC and/or MUC6, absence of CD10, and absent or low expression of CDX2); hybrid (gastric and intestinal markers); and null.Methods Sixty-six cases of nonpolypoid epithelial dysplasia of the stomach were classified according to morphological features (histotype and grade) and immunophenotype. Immunohistochemical staining was performed with antibodies against MUC2, MUC5AC, MUC6, CD10, CDX2, chromogranin, synaptophysin, Ki-67, and TP53. HER2 alterations were analyzed by immunohistochemistry and silver-enhanced in situ hybridization.Results By conventional histology, dysplasia was classified as adenomatous/intestinal (n = 42; 64 %) and foveolar or pyloric/gastric (n = 24; 36 %) and graded as low grade (n = 37; 56 %) or high grade (n = 29; 44 %). Immunophenotypic classification showed intestinal (n = 22; 33.3 %), gastric (n = 25; 37.9 %), hybrid (n = 17; 25.8 %), or null (n = 2; 3.0 %) phenotypes. In 20 cases a coexistent intramucosal carcinoma was identified. The intestinal immunophenotype was shown to be significantly associated with low-grade dysplasia (p = 0.001), high expression of CDX2 (p = 0.015), TP53 (p = 0.034), synaptophysin (p = 0.003), and chromogranin (p \ 0.0001); the gastric immunophenotype was significantly associated with high-grade dysplasia (p = 0.001), high Ki-67 proliferative index (p = 0.05), and coexistence of intramucosal carcinoma (p = 0.013). HER2 amplification was observed in 3 cases, typed as gastric or hybrid. Conclusions Epithelial nonpolypoid dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness and may represent the putative precursor lesion in a pathway of gastric carcinogenesis originated de novo from the native gastric mucosa, leading to gastric-type adenocarcinoma.

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“…In der Primärpublikation wurde bei verschiedenen Familienmitgliedern eine prophylaktische Gastrektomie durchgeführt, allein schon weil die endoskopische Überwachung bzw. Karzinomfrüherkennung bei ausgepräg-ter Polypose problematisch ist [49].…”

Section: Hereditäres Magen-und Pankreaskarzinomunclassified

Hereditäres Magen- und Pankreaskarzinom

Langner

2017

Pathologe

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Die Karzinome des Magens und des Pankreas zählen zu den häufigsten malignen Tumoren im Bereich der Viszeralonkologie. Sie tragen weltweit erheblich zur Karzinommortalität bei [46]. Im Magen werden für die Entstehung des intestinalen Typs (nach Laurén) vorwiegend Umweltfaktoren verantwortlich gemacht, in erster Linie die Infektion mit Helicobacter pylori. Für die Entstehung des diffusen Typs sind genetische Faktoren von grö-ßerer Bedeutung [38,48]. Die meisten Karzinome des Pankreas entstehen sporadisch. Erbliche Faktoren werden für 5-10 % der Tumoren verantwortlich gemacht [16,34]. Erbliches MagenkarzinomDie Mehrzahl der Magenkarzinome tritt sporadisch auf. Eine familiäre Häufung wird bei etwa 10 % der Fälle beobachtet. Nur 1-3 % weisen einen gesicherten Erbgang auf [47].Zwei erbliche Magenkarzinomsyndrome wurden beschrieben: das hereditäre diffuse Magenkarzinom (engl. "hereditary diffuse gastric cancer" [HDGC] Hereditäres diffuses MagenkarzinomIm Jahre 1998 wurden 3 neuseeländi-sche Maori-Familien beschrieben, bei denen über mehrere Generationen im frü-hen Lebensalter ein diffuses Magenkarzinom aufgetreten war. Mutationen im CDH1-Gen wurden als verantwortlicher Gendefekt identifiziert [20]. Die Vererbung erfolgt autosomal dominant. Wie wir heute wissen, handelt es sich überwie-gend um Frameshiftmutationen (38 %), aber auch Splice-site-(23 %), Missense-(17 %) und Nonsense-(17 %) Mutationen werden gefunden; große genomische Rearrangements sind selten [33]. [27,47]. E-CadherinIm Gastrointestinaltrakt können verschiedene nichtneoplastische (entzündli-che und nichtentzündliche)Veränderun-gen eine an Siegelringzellen erinnernde Morphologie ("Pseudosiegelringzellen") zeigen [14]. Hier ist besondere Vorsicht geboten, die Diagnosestellung hat sich an strikten Kriterien zu orientieren, eine Überdiagnose ist zu vermeiden [47].Die Expression von E-Cadherin ist bereits beim In-situ-Karzinom reduziert (eventuell "dot-like") oder fehlend, sodass die Inaktivierung von E-Cadherin als ein frühes Ereignis gesehen werden kann [10]. Dieses ist aber nicht in allen Fällen der Fall und hängt u. a. auch vom Typ der Mutation ab [47].Zu beachten ist, dass Mitosen seltener als in der umgebenden nichtneoplastischen Mukosa gefunden werden. Auch der Proliferationsmarker Ki67 (MIB-1) färbt die In-situ-Läsionen und die frühinvasiven Tumorherde zumeist nur schwach an, sodass dieser Marker nicht zur Diagnosesicherung geeignet ist [47].

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Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome

Cited by 255 publications

References 30 publications

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggressiveness

Hereditäres Magen- und Pankreaskarzinom

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