Hereditary Diffuse Gastric Cancer Syndrome and the Role of <i>CDH1</i>

Gamble, Lauren A.; Heller, Theo; Davis, Jeremy L.

doi:10.1001/jamasurg.2020.6155

Cited by 45 publications

(35 citation statements)

References 58 publications

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“…Approximately 20% of colorectal cancer and 5% to 10% of gastric cancer are associated with familial clustering, and most of them are associated with inherited cancer predisposition syndromes. A family history of hereditary diffuse gastric cancer (HDGC), familial adenomatous polyposis, and Lynch syndrome predisposes young people to develop gastric cancer and colorectal cancer[ 31 , 32 ]. HDGC is an autosomal dominant syndrome arising from germline mutations in the tumor suppressor gene CDH1 (encoding the cell-to-cell adhesion protein E cadherin).…”

Section: Discussionmentioning

confidence: 99%

“…HDGC is an autosomal dominant syndrome arising from germline mutations in the tumor suppressor gene CDH1 (encoding the cell-to-cell adhesion protein E cadherin). HDGC is characterized by the development of gastric cancers, predominantly the diffuse type, at a young age[ 31 ]. Genetic susceptibility also appears to be more prevalent among young colorectal patients, with a prevalence of germline mutations of 16%–33% among those diagnosed before age 50[ 32 ].…”

Section: Discussionmentioning

confidence: 99%

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Digestive cancer incidence and mortality among young adults worldwide in 2020: A population-based study

Li¹

2022

WJGO

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BACKGROUND Digestive cancer has traditionally been thought of as a disease that mainly occurs in elderly individuals, and it has been ignored in young adults by both patients and physicians. AIM To describe the worldwide profile of digestive cancer incidence, mortality and corresponding trends among 20–39-year-olds, with major patterns highlighted by age, sex, development level, and geographical region. METHODS I performed a population-based study to quantify the burden of young adult digestive cancers worldwide. Global, regional, sex, and country-specific data estimates of the number of new cancer cases and cancer-associated deaths that occurred in 2020 were extracted from the GLOBOCAN Cancer Today database. To assess long-term trends in young adult digestive cancer, cancer incidence data and mortality data were obtained from the Cancer in Five Continents Plus database and the World Health Organization mortality database, respectively. The associations between the human development index (HDI) and digestive cancer burden in young adults were evaluated by linear regression analyses. RESULTS In 2020, there were an estimated 19292789 new cancer cases, resulting in 9958133 deaths worldwide, which equated to an age-standardized incidence rate (ASIR) of 5.16 and age-standardized mortality rate (ASMR) of 3.04, accounting for 12.24% of all new cancer cases and 25.26% of all cancer deaths occurring in young adults. The burden was disproportionally greater among males, with male: female ratios of 1.34 for incidence and 1.58 for mortality. The ASIRs were 2.1, 1.4, and 1.0 per 100000 people per year, whereas the ASMRs were 0.83, 1.1, and 0.62 per 100000 people per year for colorectal, liver, and gastric cancer, respectively. When assessed by geographical region and HDI levels, the cancer profile varied substantially, and a strong positive correlation between the mortality-to-incidence ratio of digestive cancer and HDI ranking was found ( R 2 = 0.7388, P < 0.001). CONCLUSION The most common digestive cancer types are colorectal, liver and gastric cancer. The global digestive cancer burden among young adults is greater among males and exhibits a positive association with socioeconomic status. The digestive cancer burden is heavy in young adults, reinforcing the need for primary and secondary prevention strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Digestive cancer incidence and mortality among young adults worldwide in 2020: A population-based study

Li¹

2022

WJGO

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“…For example, specifically in the context of CDH1 mutation carriers, most asymptomatic individuals do not have macroscopic lesions on endoscopic examinations; however, intramucosal foci of gastric cancer, usually multiple, are observed in the surgical specimens. Therefore, it is recommended that one perform prophylactic total gastrectomy in carriers of a pathogenic variant who are older than 20 years [36,37]. Annual endoscopic screening is reserved for individuals who do not accept prophylactic gastrectomy, patients with a variant of uncertain significance, and patients in whom the germline mutation has not been identified.…”

Section: Discussionmentioning

confidence: 99%

Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study

Pocurull

Herrera‐Pariente

Carballal

et al. 2021

Cancers

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Gastric adenocarcinoma (GC) is a common tumor with high morbidity and mortality. Only 7% of patients with GC are diagnosed before age 50 (early onset gastric cancer (EOGC)), and their characteristics have been poorly described. We aimed to describe clinical, molecular, and genetic characteristics of EOGC. A total of 309 patients with EOGC were retrospectively studied in four Spanish centers. Personal information, family history, and tumor information were registered. Germinal genetic analysis was performed in patients who met current criteria of a hereditary syndrome at the time of diagnosis. The median age at diagnosis was 44 years. The majority (73.3%) of tumors were diffuse, and 78.3% were diagnosed in an advanced stage. Familial aggregation of GC was present in 18/117 (15.4%) cases, and 5/117 (4.3%) met criteria for familial GC. MMR-IHC was performed in 126/309 (40.7%) tumors: 4/126 (3.1%) had loss of expression in MLH1/PMS2, without an associated germline mutation. Sixteen germline genetic analyses were performed, detecting a pathogenic variant in four (25%) cases: one in BRCA2, one in TP53, and two in CDH1. Most EOGC are diffuse and diagnosed in an advanced stage. In these patients, DNA MMR system deficiency is uncommon. Although familial aggregation was observed in only 15% of cases, a germline mutation was found in 25% of patients tested with clinical criteria. This demonstrates that EOGC has a marked genetic heterogeneity, reinforcing the importance of an accurate genetic counseling and enhancing the emerging use of multigene panels.

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“…DGC is specifically associated with somatic or hereditary defects in the cadherin 1 (CDH1) gene, which encodes E-cadherin, and is caused by inactivating gene mutations and/or transcriptional silencing by hypermethylation in its promoter site (8,9,(13)(14)(15)(16). Notably, germline mutations or copy number variations in the CDH1 gene have been identified in 12-38% of diagnosed hereditary DGC (8,17). Furthermore, in sporadic DGC cases, somatic mutations of the CDH1 gene are more frequently detected in early-onset than late-onset DGC (18).…”

Section: Aberrant Expression Of Sfrp1 Sfrp3 Dvl2 and Dvl3 Wnt Signaling Pathway Components In Diffuse Gastric Carcinomamentioning

confidence: 99%

“…Furthermore, in sporadic DGC cases, somatic mutations of the CDH1 gene are more frequently detected in early-onset than late-onset DGC (18). Additionally, a number of studies have demonstrated the association of variations in the Ras homolog family member A (RHOA) gene, such as mutations and amplifications, and changes in its transcriptional activation (resulting in protein upregulation) with specific clinicopathological characteristics of the DGC subtype (17)(18)(19)(20)(21).…”

Section: Aberrant Expression Of Sfrp1 Sfrp3 Dvl2 and Dvl3 Wnt Signaling Pathway Components In Diffuse Gastric Carcinomamentioning

confidence: 99%

Aberrant expression of SFRP1, SFRP3, DVL2 and DVL3 Wnt signaling pathway components in diffuse gastric carcinoma

et al. 2021

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Diffuse gastric carcinoma (DGC) is characterized by poorly cohesive cells, highly invasive growth patterns, poor prognosis and resistance to the majority of available systemic therapeutic strategies. It has been previously reported that the Wnt/β-catenin signaling pathway serves a prominent role in the tumorigenesis of gastric carcinoma. However, the mechanism underlying the dysregulation of this pathway in DGC has not been fully elucidated. Therefore, the present study aimed to investigate the expression profiles of Wnt antagonists, secreted frizzled-related protein 1 (SFRP1) and secreted frizzled-related protein 3 (SFRP3), and dishevelled protein family members, dishevelled segment polarity protein 2 (DVL2) and dishevelled segment polarity protein 3 (DVL3), in DGC tissues. The association between the expression levels of these factors and the clinicopathological parameters of the patients was determined. Protein and mRNA expression levels in 62 DGC tumor tissues and 62 normal gastric mucosal tissues obtained from patients with non-malignant disease were measured using immunohistochemical and reverse transcription-quantitative PCR (RT-qPCR) analysis. Significantly lower protein expression levels of SFRP1 (P<0.001) and SFRP3 (P<0.001), but significantly higher protein expression levels of DVL2 (P<0.001) and DVL3 (P<0.001) were observed in DGC tissues compared with in control tissues by immunohistochemistry. In addition, significantly lower expression levels of SFRP1 (P<0.05) and higher expression levels of DVL3 (P<0.05) were found in in DGC tissues compared with those in normal gastric mucosal tissues using RT-qPCR. According to correlation analysis between the SFRP1, SFRP3, DVL2 and DVL3 protein expression levels and the clinicopathological characteristics of patients with DGC, a statistically significant correlation was found between the SFRP3 volume density and T stage (r=0.304; P=0.017) and between the SFRP3 volume density and clinical stage (r=0.336; P=0.008). In conclusion, the findings of the present study suggested that the Wnt signaling pathway components SFRP1, SFRP3, DVL2 and DVL3 may be aberrantly expressed in DGC tissues, implicating their possible role in the development of this malignant disease. The present data also revealed a positive relationship between SFRP3 protein expression and the clinical and T stage of DGC.

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Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1

Cited by 45 publications

References 58 publications

Digestive cancer incidence and mortality among young adults worldwide in 2020: A population-based study

Digestive cancer incidence and mortality among young adults worldwide in 2020: A population-based study

Clinical, Molecular and Genetic Characteristics of Early Onset Gastric Cancer: Analysis of a Large Multicenter Study

Aberrant expression of SFRP1, SFRP3, DVL2 and DVL3 Wnt signaling pathway components in diffuse gastric carcinoma

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