Germline Mutations in CDH1 and the Hereditary Diffuse Gastric and Lobular Breast Cancer Syndrome

Benusiglio, Patrick R.; Malka, David; Pauw, Antoine de; Bruno, Benedetto; Rouleau, Étienne; Colas, Chystelle; Grandjouan, S.; Blayau, Martine; Delaloge, Suzette; Caron, Olivier; Machado, Patrícia Maria Abreu; Clara, Ana; Mayer, Astrid; Fragoso, Sofia; Santos, S.; Luis, A Sales; Opinião, A.; Parreira, Joana; Simões, Camila; Vaz, Fátima; Musolino, Antonino; Bella, Maria Angela; Michiara, Maria; Zanelli, Paola; Naldi, Nadia; Bortesi, Beatrice; Sgargi, Paolo; Camisa, Roberta; Neri, Tauro Maria; Ardizzoni, Andrea; Alexandre, Marie; Bento, Sandra; Fontana, Ana Paula; Aretini, Paolo; Ferrarini, Ilaria; Bona, Enrico Dalla; Stasi, I.; Landucci, Elisa; Allegrini, Giacomo; Roncella, Manuela; Caligo, Ma; Falcone, Alfredo; Cadoo, K.A.; Noonan, Sinéad; McNicholas, Nuala; Kennedy, Michael J.; Márquez-Rodas, Iván; Blanco, Ana; Moya, Beatriz; Cabello, Sara Custodio; Ramírez, Sara; Cavanagh, M.; López-Trabada, Daniel; López-Tarruella, Sara; Jerez, Yolanda

doi:10.1093/annonc/mds396

Cited by 26 publications

(36 citation statements)

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“…In fact, the initial approaches to assess the pathogenicity of the c.1679C>G variant (through in silico predictions, familial segregation, and population frequencies) suggested the involvement of the variant in HDGC. Furthermore, this variant had been reported twice before in the literature-in a young patient with DGC [5] and in a family of Indian origin also with DGC [6]-together with two unpublished cases reported to the Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP; personal communication from R Seruca, 2016). Benusiglio et al did not perform any type of functional analysis [5], while Yelskaya et al described that the c.1679C>G variant disrupts normal splicing, which presumably leads to truncation of the protein [6].…”

Section: Discussionmentioning

confidence: 87%

“…Furthermore, this variant had been reported twice before in the literature-in a young patient with DGC [5] and in a family of Indian origin also with DGC [6]-together with two unpublished cases reported to the Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP; personal communication from R Seruca, 2016). Benusiglio et al did not perform any type of functional analysis [5], while Yelskaya et al described that the c.1679C>G variant disrupts normal splicing, which presumably leads to truncation of the protein [6]. In support of these findings, we also observed that the c.1679C>G change generates an alternative 5′ splice site, leading to the loss of 32 nucleotides in exon 11 or to a premature stop codon at position 576 of the protein.…”

Section: Discussionmentioning

confidence: 87%

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Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer

et al. 2018

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Germline changes in the CDH1 tumor suppressor gene predispose to diffuse gastric cancer and lobular breast cancer. In carriers of deleterious germline CDH1 variants, prophylactic gastrectomy is recommended. In case of germline missense variants, it is mandatory to assess the functional impact on E-cadherin, the protein encoded by CDH1, and to predict their clinical significance. Herein, we have identified a recurrent germline missense variant, c.1679C>G, segregating with gastric cancer in three unrelated Spanish families. Through genetic, transcriptional, in silico and in vitro studies, we demonstrate the deleterious effect of the c.1679C>G variant and its association with hereditary diffuse gastric cancer, providing relevant data to relatives and allowing an accurate genetic counseling.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 87%

Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer

et al. 2018

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“…Germline CDH1 alterations are not restricted to specific sites of the CDH1 gene or specific E-cadherin protein domains, as they are distributed throughout the coding regions and include splice-site sequences and UTRs (5'-and 3'-untranslated regions) of the gene, as well as throughout all protein functional domains [67]. Penetrance in proven mutation carriers is incomplete, with an estimated lifetime risk for DGC of >80% in both men and women by age 80 and of 60% for lobular breast cancer in women by the age of 80 [67].…”

Section: Hereditary Gastric Cancermentioning

confidence: 99%

The Role of Genetic Instability in Familial Cancer Syndromes

Economopoulou¹

2013

J Genet Syndr Gene Ther

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Familial cancer syndromes have been model diseases in order to understand the mechanisms and process of neoplastic transformation in a number of solid tumors, including colorectal, breast, ovarian, gastric and others. Basic experimentation in hereditary cancer genetics has been interpolated into important hypotheses about carcinogenesis in humans. Overtime, evolution of molecular genetics and clarification of the functional structure of the human genome has led to the identification of familial cancer-causing germline mutations. At present, approximately 100 genes (corresponding to 0.5% of all genes in the human genome) exhibit mutations with low or high penetration, which underlie hereditary cancer syndromes. Furthermore, sequencing of complete cancer genomes across a wide range of human tumors has shown that common human cancers possess numerous somatic mutations in their genomes that might contribute to the neoplastic process. This review discusses the role of genomic instability in tumorigenesis through the model of familial cancer syndromes and their potential implications in the clinic.

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“…Hereditary diffuse gastric cancer (HDGC) is a cancer predisposition syndrome which accounts for up to 19-40% of familial gastric cancers and is associated with an autosomal-dominant inheritance pattern due to germline CDH1 variants [1][2][3]. While initially a syndrome used to describe familial inheritance of diffuse gastric cancer, it is now recognized that the syndrome includes increased risk for lobular breast cancer (LBC), possibly colorectal cancer, and non-cancerous but significant conditions like cleft lip palate syndrome [2][3][4][5][6][7][8]. Lifetime cumulative risk for gastric cancer in male CDH1 mutation carriers is 70% by age 80; similar risk for female CDH1 mutation carriers is 56% for diffuse gastric cancer and 42% for LBC [3].…”

Section: Introductionmentioning

confidence: 99%

Merging perspectives: genotype‐directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E‐cadherin–EGFR crosstalk

Li¹,

Rudloff³

2018

Clinical & Translational Med

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Hereditary diffuse gastric cancer is a cancer predisposition syndrome associated with germline mutations of the E-cadherin gene (CDH1; NM_004360). Male CDH1 germline mutation carriers have by the age of 80 years an estimated 70% cumulative incidence of gastric cancer, females of 56% for gastric and of 42% for lobular breast cancer. Metastatic HDGC has a poor prognosis which is worse than for sporadic gastric cancer. To date, there have been no treatment options described tailored to this molecular subtype of gastric cancer. Here we review recent differential drug screening and gene expression results in c.1380del CDH1-mutant HDGC cells which identified drug classes targeting PI3K (phosphoinositide 3-kinase), MEK (mitogen-activated protein kinase), FAK (focal adhesion kinase), PKC (protein kinase C), and TOPO2 (topoisomerase II) as selectively more effective in cells with defective CDH1 function. ERK1-ERK2 (extracellular signal regulated kinase) signaling measured as top enriched network in c.1380delA CDH1-mutant cells. We compared these findings to synthetic lethality and pharmacological screening results in isogenic CDH1 −/− MCF10A mammary epithelial cells with and without CDH1 expression and current knowledge of E-cadherin/catenin–EGFR cross-talk, and suggest different rationales how loss of E-cadherin function activates PI3K, mTOR, EGFR, or FAK signaling. These leads represent molecularly selected treatment options tailored to the treatment of CDH1-deficient familial gastric cancer.

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Germline Mutations in CDH1 and the Hereditary Diffuse Gastric and Lobular Breast Cancer Syndrome

Cited by 26 publications

References 0 publications

Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer

Clinical and functional characterization of the CDH1 germline variant c.1679C>G in three unrelated families with hereditary diffuse gastric cancer

The Role of Genetic Instability in Familial Cancer Syndromes

Merging perspectives: genotype‐directed molecular therapy for hereditary diffuse gastric cancer (HDGC) and E‐cadherin–EGFR crosstalk

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