Early HER2 dysregulation in gastric and oesophageal carcinogenesis

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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“…These findings show that HER2 amplification may be an early event in gastric carcinogenesis, as observed by Fassan et al [21].…”

Section: Discussionsupporting

confidence: 71%

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

et al. 2014

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“…While dysplasia is an effective biomarker of malignant potential in Barrett’s esophagus [1], diagnostic accuracy is limited by biopsy sampling error and interobserver disagreement, which may be occur in up to 15% of cases for high-grade dysplasia [22]. This may explain, in part, the lower rate of HER2 expression in this study, as compared to a previously published analysis [3,4]. Second, the results cannot be extrapolated to the setting of Barrett’ esophagus without dyplasia.…”

Section: Discussionmentioning

confidence: 74%

HER3 Expression Is a Marker of Tumor Progression in Premalignant Lesions of the Gastroesophageal Junction

et al. 2016

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Overexpression of receptor tyrosine kinases (RTK), including members of the HER family, has prognostic and therapeutic significance in invasive esophagogastric carcinoma. RTK expression in premalignant gastroesophageal lesions has not been extensively explored. Formalin-fixed paraffin-embedded tissue samples of esophageal biopsy specimens from 73 patients with Barrett’s esophagus with either low-grade dysplasia (LGD) (n = 32) or high-grade dysplasia (HGD) (n = 59) were analyzed for HER1, HER2, HER3 and CMET expression by immunohistochemistry (IHC). Immunophenotype was correlated with histologic and clinical features. High-grade dysplasia (HGD) was associated with overexpression of HER1 (20.7% vs. 3.1%, p = 0.023), HER2 (5.3% vs. 0.0%, p = 0.187) and HER3 (47.4% vs. 9.4%, p<0.001) compared to low-grade dysplasia (LGD). There was a significant association of HER2 (20.0% vs. 2.1%, p = 0.022) and HER3 (80.0% vs. 40.4%, p = 0.023) overexpression in HGD lesions associated with foci of invasive carcinoma compared to those without invasive foci. Overexpression of CMET was observed in 42.9% of specimens, was increasingly observed with HGD compared to LGD (58.3% vs. 36.7%, p = 0.200), and was most often co-expressed with HER3 (62.5% of HER3-positive specimens vs. 38.2% of HER3-negative specimens, p = 0.212). In summary, HER3 is frequently overexpressed in high-grade dysplastic lesions of the gastroesophageal junction and may be a marker of invasive progression. These data provide rationale for targeting HER2 and HER3 pathways in an early disease setting to prevent disease progression.

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“…Moreover, most of the limited amount of material obtained from upper GI endoscopy is required for histopathological characterization of the specimen. As a result, there is still no molecular marker used in clinical practice to distinguish HG-IEN from early invasive neoplasia [17][18][19][20].…”

Section: Discussionmentioning

confidence: 99%

High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers

et al. 2013

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Background There is still no widely accepted molecular marker available to distinguish between gastric high-grade intraepithelial neoplasia (HG-IEN) and invasive early gastric cancer (EGC). Methods HG-IEN and EGC lesions coexisting in the same patient were manually microdissected from a series of 15 gastrectomies for EGC; 40 ng DNA was used for multiplex PCR amplification using the Ion AmpliSeq Cancer Panel, which explores the mutational status of hotspot regions in 50 cancer-associated genes. Results Of the 15 EGCs, 12 presented at least one somatic mutation among the 50 investigated genes, and 6 of these showed multiple driver gene somatic mutations. TP53 mutations were observed in 9 cases; APC mutations were identified in 3 cases; and ATM and STK11 were mutated in 2 cases. Seven HG-IEN lesions shared an identical mutational profile with the EGC from the same patient; 13 mutations observed in APC, ATM, FGFR3, PIK3CA, RB1, STK11, and TP53 genes were shared by both HG-IEN and ECG lesions. CDKN2A, IDH2, MET, and RET mutations were observed only in EGC. TP53 deregulation was further investigated in an independent series of 75 biopsies corresponding to all the phenotypic lesions occurring in the EGC carcinogenetic cascade. p53 nuclear immunoreaction progressively increased along with the dedifferentiation of the lesions (P \ 0.001). Overall, 18 of 20 p53-positive lesions showed a TP53 mutated gene. Discussion Our results support the molecular similarity between HG-IEN and EGC and suggest a relevant role for TP53 in the progression to the invasive phenotype and the use of immunohistochemistry as a surrogate to detect TP53 gene mutations.

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Early HER2 dysregulation in gastric and oesophageal carcinogenesis

Abstract: There is early involvement of HER2 dysregulation (amplification and protein overexpression) in both gastric (intestinal-type) and Barrett's oncogenesis.

Cited by 63 publications

References 27 publications

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

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

HER3 Expression Is a Marker of Tumor Progression in Premalignant Lesions of the Gastroesophageal Junction

High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers

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