Supplementary Figure 4 from Early Immune Changes Support Signet Ring Cell Dormancy in <i>CDH1</i>-Driven Hereditary Diffuse Gastric Carcinogenesis
Benjamin L. GreenLauren A. GambleLaurence P. DiggsDarryl NousomeJesse C. PattersonBrian A. JoughinBillel GasmiStephanie C. LuxSarah G. SamaranayakeMarkku MiettinenMartha QuezadoJonathan M. HernandezMichael B. YaffeJeremy L. Davis
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<p>GSEA plots comparing (A) oxidative phosphorylation, (B) glycolysis, and (C) fatty acid oxidation gene sets in SRC compared with NEP.</p>Keywords:
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Invasive lobular carcinoma
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Invasive lobular carcinoma (ILC) of the breast is believed to develop from in situ lesions, atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Down-regulation of the cell-cell adhesion protein E-cadherin is a defining feature of lobular breast cancer (LBC) and already occurs in ALH and LCIS. Apart from mutational mechanisms, epigenetic silencing of the E-cadherin gene (CDH1) is thought to be involved in E-cadherin down-regulation and has been observed at a high frequency in ILC. Whether CDH1 promoter methylation is already present in in situ lesions and thus contributes to the initiation of LBC is not established. We thus examined microdissected archived tissue from 20 LBCs by methylation-specific PCR to determine the CDH1 methylation status of lobular lesions. Nineteen of the 20 LBCs had a hypermethylated CDH1 promoter, including 13/14 ILCs and 13/13 ALHs or LCIS. Bisulphite sequencing indicated that methylation was complete within the investigated promoter fragment. Intriguingly, CDH1 methylation was likewise present in 8/8 adjacent non-neoplastic epithelia, but not in 6/6 mammary epithelia from healthy subjects. E-cadherin protein and mRNA were down-regulated in in situ lesions relative to adjacent epithelia. Together, these results indicate that CDH1 promoter methylation occurs in LBC prior to E-cadherin down-regulation and neoplastic formation. We thus propose that epigenetic silencing represents the first of the two hits required to silence both CDH1 alleles for LBC to develop. Because promoter methylation is in principle reversible, our findings suggest that chemoprevention of LBC by epigenetic drugs should be feasible. Furthermore, the presence of CDH1 methylation in pre-neoplastic epithelia suggests the existence of mammary regions with increased disease susceptibility, providing an explanation for the often multifocal presentation of LBC.
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Lobular carcinoma
Bisulfite sequencing
Invasive lobular carcinoma
Carcinoma in situ
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Hereditary diffuse gastric cancer (HDGC), comprising 1%–3% of gastric malignances, has been associated with CDH1 variants. Accumulating evidence has demonstrated more than 100 germline CDH1 variant types. E-cadherin encoded by the CDH1 gene serves as a tumor suppressor protein. CDH1 promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic CDH1 variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in CDH1 variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.
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Abstract Background: Epithelial-mesenchymal transition (EMT) is a critical process which involves in tumor metastasis. As an important EMT marker gene, CDH1 (E-cadherin) expression and its clinical implication in acute myeloid leukemia (AML) remain largely elusive. Methods: Real-time quantitative PCR (RQ-PCR) was carried out to examine CDH1 transcript level in 123 de novo AML patients and 34 controls. Results: Compared with controls, CDH1 was significantly downregulated in AML (p<0.001). The median level of CDH1 expression divided total AML patients into CDH1 low-expressed ( CDH1 1ow ) and CDH1 high-expressed ( CDH1 high ) groups. There were no significant differences between the two groups in age, peripheral blood cell counts, complete remission (CR) rate, and the distribution of FAB/WHO subtypes as well as karyotypes/karyotypic classifications (p>0.05). However, CDH1 1ow group tended to have a higher bone marrow (BM) blasts (p=0.093). The spearman correlation analysis further illustrated a trend towards a negative correlation between CDH1 expression level and BM blasts (r=–0.214, p=0.052). CDH1 low group had a tendency towards a lower frequency of N/K-RAS mutations (p=0.094). Furthermore, CDH1 low patients had markedly shorter overall survival (OS) time in cytogenetic normal AML (CN-AML) (p=0.019). Both univariate and multivariate analyses confirmed the prognostic value of CDH1 expression in CN-AML patients (p=0.027 and 0.033, respectively). Conclusions: CDH1 downregulation acted as an independent prognostic biomarker in CN-AML patients.
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Dormancy in bulbs describes a complex phenomenon involving temporal cessation of growth in metabolically active plant parts until the conditions become favourable. The entire physiology of metabolic arrest with its induction and termination is under hormonal, molecular and environmental control. At present, the molecular regulation of dormancy is still remains unclear and least understood. Indian floriculture industry totally depends on import of flower bulbs every year due to the development of deep dormancy in bulbs. Dormant bulb requires an ample of cold treatment period to release its dormancy. Moreover, dormancy limits the production immediately after harvest and importing of bulbs from the other countries increases the chances of entry of exotic pests and diseases which challenges our farmer's economy. To overcome this problem, necessary treatments are required to practice for easy sprouting by modulating the biosynthetic pathway of inhibitory substances.
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Dormancy of temperate zone deciduous fruit trees allow the trees to reserve cold climate conditions during the winter. Recent years' study indicates that dormancy can not only let fruit trees survive cold winter, but be a necessary procedure for deciduous fruit trees to bloom and fruit normally next year. The definition of dormancy process, the determination of dormancy depth and the effect of temperature on dormancy are the theoretical foundation of fruit trees bud dormancy study. The dormancy of deciduous fruit trees could be divided into three parts, para dormancy, endo dormancy and eco dormancy. Low temperature could improve to break dormancy There are three methods to determinate the end time of fruit trees bud dormancy: 7.2℃ low temperature model, Utah model and dynamic model. But there are two different reviews about the effect of high temperature: some believe that high temperature could counteract the effect of low temperature, others believe that high temperature could improve to break dormancy.
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Background: Aberrant promoter hypermethylation has been recognized in human breast carcinogenesis as a frequent molecular alteration associated with the loss of expression of a number of key regulatory genes and may serve as a biomarker. The E-cadherin gene (CDH1), mapping at chromosome 16q22, is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. The aim of our study was to assess the methylation pattern of CDH1 and to correlate it with the expression of E-cadherin, clinicopathological parameters and hormone receptor status in breast cancer patients of Kashmir. Materials and Methods: Methylation specific PCR (MSP) was used to determine the methylation status of CDH1 in 128 invasive ductal carcinomas (IDCs) paired with the corresponding normal tissue samples. Immunohistochemistry was used to study the expression of E-cadherin, ER and PR. Results: CDH1 hypermethylation was detected in 57.8% of cases and 14.8% of normal adjacent controls. Reduced levels of E-cadherin protein were observed in 71.9% of our samples. Loss of E-cadherin expression was significantly associated with the CDH1 promoter region methylation (p<0.05, OR=3.48, CI: 1.55-7.79). Hypermethylation of CDH1 was significantly associated with age at diagnosis (p=0.030), tumor size (p=0.008), tumor grade (p=0.024) and rate of node positivity or metastasis (p=0.043). Conclusions: Our preliminary findings suggest that abnormal CDH1 methylation occurs in high frequencies in infiltrating breast cancers associated with a decrease in E-cadherin expression. We found significant differences in tumor-related CDH1 gene methylation patterns relevant to tumor grade, tumor size, nodal involvement and age at diagnosis of breast tumors, which could be extended in future to provide diagnostic and prognostic information.
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Abstract Introduction: Invasive lobular carcinoma (ILC) is the most prevalent histologic special type of breast cancer, representing ~15% of invasive breast cancers. ILCs are mostly hormone receptor-positive and diagnosed histologically based on their distinctive discohesive growth pattern, dispersed single cells or line of cells invading the stroma. ILCs commonly show biallelic inactivation of a CDH1 (~65%), a tumor suppressor gene that is mapped to 16q22.1 and encodes for E-cadherin, a critical component of the epithelial adhesion complex. Massively parallel sequencing and pathologic studies have shown that a subset of ILCs (up to 15%) may lack CDH1 loss-of-function (LOF) mutations/deletions and retain E-cadherin expression, despite their distinctive lobular phenotype. The genetic and epigenetic underpinning of ILCs lacking CDH1 alterations has yet to be defined. Here we sought to define the mechanistic basis of the lobular phenotype in ILCs lacking CDH1 LOF genetic alterations or CDH1 gene promoter methylation and to determine the repertoire of epigenetic and genetic alterations of CDH1-wildtype ILCs. Materials and methods: Reanalysis of the CDH1 gene status in 364 primary ILCs, previously subjected to clinical massively parallel sequencing, was performed to identify all primary ILCs lacking bi-allelic CDH1 alterations. The hematoxylin and eosin stained slides of all identified ILCs lacking bi-allelic CDH1 alterations were reviewed by two pathologists and primary pure ILCs lacking bi-allelic CDH1 alterations were curated. We evaluated the presence of genetic alterations in genes playing essential roles in epithelial adhesion included in the clinical sequencing panel of up to 505 genes. The presence of CDH1 promoter methylation in 18 ILCs lacking bi-allelic CDH1 alterations with available formalin-fixed, paraffin-embedded (FFPE) material was assessed using methylation-specific PCR (MSP) and bisulfite sequencing. Results: We identified 23/364 (6.3%) primary ILCs lacking bi-allelic CDH1 alterations, of which 65.3% and 34.7% were classic and pleomorphic lobular variants, respectively. In 18 cases with available FFPE material, our analyses revealed that 67% (12/18) of ILCs lacking bi-allelic CDH1 alterations displayed biallelic CDH1 inactivation via promoter methylation and 16q loss. Furthermore, we observed that 1/23 ILC lacking bi-allelic CDH1 alterations had bi-allelic inactivation of AXIN2. We then extended our query to all invasive breast carcinomas subjected to clinical sequencing, including the ones initially categorized as invasive breast carcinoma “type unknown”, and observed that the three additional cases with pathogenic LOF AXIN2 alterations were ILCs lacking bi-allelic CDH1 alterations. Conclusions: The lobular phenotype in ILCs can be due to CDH1 promoter methylation or genetic alterations affecting other genes related to epithelial cell adhesion, such as AXIN2 LOF mutations. Whole-genome sequencing analyses of ILCs whose molecular basis has not been identified by targeted sequencing are warranted. Citation Format: Fatemeh Derakhshan, Higinio Dopeso, Arnaud Da Cruz Paula, Pier Selenica, Antonio Marra, Edaise M da Silva, Andrea Gazzo, Shirin Issa Bhaloo, Dara S Ross, Anne Grabenstetter, Sarat Chandarlapaty, Pedram Razavi, Hannah Y. Wen, Hong Zhang, Edi Brogi, Britta Weigelt, Fresia Pareja, Jorge S. Reis-Filho. Genetic and epigenetic basis of invasive lobular carcinomas lacking CDH1-alterations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-03.
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Objective:To investigate CDH1 methylation of epithelial-cadherin(E-cadherin) gene in intrahepatic cholangiocarcinomas (ICCs). Methods: Forty-two liver samples were obtained from ICC patients (32 males and 10 females) during surgical resection in Eastern Hepatobiliary Surgery Hospital. The ICC tissue samples and the adjacent tissue samples were paraffin-embedded and fresh ice-frozen. A methylation-specific polymerase chain reaction (MSP) was used for analyzing the methylation of CDH1 gene; E-cadherin protein and mRNA expression was detected by immunohistochemical method and RT-PCR analysis, respectively. Results: The methylation rate of CDH1 was 28.6% in ICC patients. The expression of E-cadherin mRNA and protein was decreased in 64.3% and 69.1% of the samples, respectively. The methylation of CDH1 gene was correlated with the expression of E-cadherin protein and mRNA and metastasis of ICCs (P=0.008, P=0.031, and P=0.020, respectively),but not with the prognosis of ICC. The abnormal expression of E-cadherin was significantly correlated with the survival of patients(P=0.002). Conclusion: The methylation of CDH1 gene and down-regulation of E-cadherin are frequently seen in ICC patients, indicating that they may be closely related to the development and progression of ICCs.
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Intrahepatic Cholangiocarcinoma
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