Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer

José, Celina São; Garcia-Pelaez, José; Ferreira, Marta; Arrieta, Óscar; André, Ana; Martins, N.; Solís, S; Martínez‐Benitez, Braulio; Ordóñez-Sánchez, María Luisa; Rodrı́guez-Torres, Maribel; Sommer, Anna; Paske, Iris B A W Te; Caldas, Carlos; Tischkowitz, Marc; Tusié, Maria Teresa; Hoogerbrugge, Nicoline; Demidov, German; Voer, Richarda M. de; Laurie, Steve; Oliveira, Carla

doi:10.1007/s10120-023-01395-0

Cited by 5 publications

(3 citation statements)

References 73 publications

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“…Importantly, targeted genetic testing has now been made available to their offspring to avoid unnecessary prophylactic gastrectomy in subsequent generations. The functional analysis and clinical implications of this CNV are described in more detail in São José et al 32 .…”

Section: Resultsmentioning

confidence: 99%

Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

Demidov,

Yaldiz,

Garcia-Pelaez

et al. 2023

Preprint

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We report the diagnostic results of a comprehensive copy number variant (CNV) reanalysis of 9,171 exome sequencing (ES) datasets from 5,757 families, including 6,143 individuals affected by a rare disease (RD). The data analysed was extremely heterogeneous, having been generated using 28 different exome enrichment kits, and sequenced on multiple short-read sequencing platforms, by 42 different research groups across Europe partnering in the Solve-RD project. Each of these research groups had previously undertaken their own analysis of the ES data but had failed to identify disease-causing variants. We applied three CNV calling algorithms to maximise sensitivity: ClinCNV, Conifer, and ExomeDepth. Rare CNVs overlapping genes of interest in custom lists provided by one of four partner European Reference Networks (ERN) were identified and taken forward for interpretation by clinical experts in RD. To facilitate interpretation, Integrative Genomics Viewer (IGV) screenshots incorporating a variety of custom-made tracks were generated for all prioritised CNVs. These analyses have resulted in a molecular diagnosis being provided for 51 families in this sample, with ClinCNV performing the best of the three algorithms in identifying disease-causing CNVs. We also identified pathogenic CNVs that are partially explanatory of the proband's phenotype in a further 34 individuals. This work illustrates the value of reanalysing ES cold cases for CNVs even where analyses had been undertaken previously. Crucially, identification of these previously undetected CNVs has resulted in the conclusion of the diagnostic odyssey for these RD families, some of which had endured decades.

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Section: Resultsmentioning

confidence: 99%

Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

Demidov,

Yaldiz,

Garcia-Pelaez

et al. 2023

Preprint

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“…[ 14 ] Actually, the differences in epidemiology and clinical, pathological, and molecular characteristics clearly exist between early-onset and late-onset cancers, however, these differences do not change dramatically at exactly 50 years older. [ 15 ] It is a limitation of applying the cutoff point of 50 years older. In a recent review, the definition of early-onset GC was defined as patients under 50.…”

Section: Discussionmentioning

confidence: 99%

Distinct characteristics of distant metastasis in early-onset gastric cancer patients compared to late-onset patients: An observational study

Wu,

Shuai

2024

Medicine

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Presently, there is limited understanding of the features of distant metastasis in early-onset gastric cancer (GC). To explore these disparities, a retrospective study utilizing the Surveillance, Epidemiology, and End Results (SEER) database was undertaken. The SEER database was utilized to extract patient data, and multivariate logistic regression analysis was employed to identify the risk factors associated with distant metastasis and liver metastasis. Propensity score matching (PSM) was used to compare the occurrence of liver metastasis among patients based on their age at diagnosis. The study included 2684 early-onset GC patients and 33,289 late-onset GC patients. Preliminary data analysis indicated that early-onset GC patients exhibited more aggressive characteristics such as poor cell differentiation, advanced T stage, and a higher incidence of distant metastasis, excluding liver metastasis. Multivariate logistic regression analysis identified younger age as an independent risk factor for distant metastasis, along with T stage, lymph node metastasis (LNM), and tumor size (>3 cm). Another regression analysis revealed that younger age, diffuse type, and female gender were protective factors against liver metastasis. Through PSM, 3276 early-onset GC patients were matched with an equal number of late-onset GC patients, revealing that patients with early-onset GC had fewer instances of liver metastasis but a higher prevalence of distant metastasis. Our findings suggest that early-onset serves as a protective factor against liver metastasis in GC, while it poses a risk for distant metastasis, likely influenced by the increased prevalence of diffuse-type GC in early-onset patients.

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“…Although occult, early-stage signet ring cell carcinoma is a common finding at RRTG, additional research is needed to elucidate the mechanisms by which some of these lesions will progress to advanced cancer and others will not. 40 , 41 Until accurate cancer risk stratification is available, the risk reduction achieved with RRTG is absolute, albeit consequential. Nearly all patients in this study exhibited at least one chronic sequela of RRTG.…”

Section: Discussionmentioning

confidence: 99%

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy

Gallanis,

Gamble,

Samaranayake

et al. 2024

JCO

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PURPOSE Risk-reducing surgery for cancer prevention in solid tumors is a pressing clinical topic because of the increasing availability of germline genetic testing. We examined the short- and long-term outcomes of risk-reducing total gastrectomy (RRTG) and its lesser-known impacts on health-related quality of life (QOL) in individuals with hereditary diffuse gastric cancer syndrome. METHODS Individuals who underwent RRTG as part of a single-institution natural history study of hereditary gastric cancers were examined. Clinicopathologic details, acute and chronic operative morbidity, and health-related QOL were assessed. Validated questionnaires were used to determine QOL scores and psycho-social-spiritual measures of healing. RESULTS One hundred twenty-six individuals underwent RRTG because of a pathogenic or likely pathogenic germline CDH1 variant between October 2017 and December 2021. Most patients (87.3%; 110/126) had pT1aN0 gastric carcinoma with signet ring cell features on final pathology. Acute (<30 days) postoperative major morbidity was low (5.6%; 7/126) and nearly all patients (98.4%) lost weight after total gastrectomy. At 2 years after gastrectomy, 94% (64/68) of patients exhibited at least one chronic complication (ie, bile reflux, dysphagia, and micronutrient deficiency). Occupation change (23.5%), divorce (3%), and alcohol dependence (1.5%) were life-altering consequences attributed to total gastrectomy by some patients. In patients with a median follow-up of 24 months, QOL scores decreased at 1 month after gastrectomy and returned to baseline by 6-12 months. CONCLUSION RRTG is associated with life-changing adverse events that should be discussed when counseling patients with CDH1 variants about gastric cancer prevention. The risks of cancer-prevention surgery should not only be judged in the context of likelihood of death due to disease if left untreated, but also based on the real consequences of organ removal.

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Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer

Cited by 5 publications

References 73 publications

Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

Comprehensive reanalysis for CNVs in ES data from unsolved rare disease cases results in new diagnoses

Distinct characteristics of distant metastasis in early-onset gastric cancer patients compared to late-onset patients: An observational study

Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy

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