Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1

Post, Rachel S. van der; Vogelaar, Ingrid P.; Manders, Peggy; Kolk, Lizet E. van der; Cats, Annemieke; Hest, Liselotte P. van; Sijmons, Rolf H.; Aalfs, Cora M.; Ausems, Margreet G. E. M.; García, Encarna B. Gómez; Wagner, Anja; Hes, Frederik J.; Arts, Neeltje; Mensenkamp, Arjen R.; Krieken, J. Han van; Hoogerbrugge, Nicoline; Ligtenberg, Marjolijn J. L.

doi:10.1053/j.gastro.2015.06.003

Cited by 75 publications

(74 citation statements)

References 63 publications

(43 reference statements)

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“…On the basis of the two cases reported in the present study, the importance of young age at cancer diagnosis should be underlined, even in a family with no known history of cancer, and genetic testing for LBC must be considered, even though the proband may not meet the most stringent selection criteria (10,17,22).…”

Section: Discussionmentioning

confidence: 96%

“…Another issue is the prognosis of these tumors. It has been suggested that a generic family history for GC may define a less aggressive cancer, compared with the pure sporadic cancer (20,21); however, recently, overall survival rate of CDH1 mutation carriers has been indicated to be worse compared with patients exhibiting wild-type CDH1, with 4 vs. 13% for 5-year survival rate (22).…”

Section: Discussionmentioning

confidence: 99%

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Hereditary diffuse gastric cancer in two families: A case report

et al. 2017

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Abstract. Hereditary diffuse gastric cancer (HDGC) is associated with E-cadherin 1 (CDH1) germline mutations. In the present study, two unusual HDGC cases are described. Case 1 was a female with no family history of gastric cancer who developed Hodgkin's lymphoma at 19 years of age, and DGC at 32 years of age. Due to her young age (32 years), the patient was examined for CDH1 abnormalities and a deleterious mutation was identified. Her father and younger sister were identified to be carriers of the mutation. Case 2 was a 36-year-old female diagnosed with lobular breast cancer (LBC); her mother had LBC, and her grandmother had LBC and DGC. The molecular test was wild-type for breast cancer susceptibility genes 1 and 2; however, a large deletion in CDH1 was identified. At prophylactic gastrectomy, early DGC was identified. Early onset of DGC and LBC justifies testing for CDH1. A better knowledge of tumor natural history in carrier subjects is important to aid genetic counseling, in order to assess the surveillance time required prior to carrying out prophylactic surgery.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Hereditary diffuse gastric cancer in two families: A case report

et al. 2017

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Section: Introductionmentioning

confidence: 99%

“…HDGC is clinically defined by the familial occurrence of early-onset diffuse gastric cancer (DGC) and lobular breast cancer [2–4]. Of the 26,370 cases of gastric cancer expected to be diagnosed in the United States in 2016, 5 to 10 percent arise in a familiar context and about 34–45% of these are due to CDH1 germline mutations [4, 5]. CDH1 germline mutations are most commonly truncating CDH1 variants affecting the extracellular domains of the E-cadherin gene leading to loss of CDH1 expression, followed by missense and splice site variants and, infrequently, large genomic deletions [2].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer

Chen

Mathews-Greiner

et al. 2017

J Transl Med

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BackgroundPatients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease.MethodsIn order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells.ResultsUnsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1–ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function.ConclusionIntegrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1197-5) contains supplementary material, which is available to authorized users.

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“…The expression of E-cadherin may be a useful immunohistochemical marker that helps to distinguish between ILC and invasive ductal carcinoma (IDC) of the breast [2]. The association of the diffuse type of gastric cancer and ILC in families with E-cadherin germline mutation is well proven [1,[3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Is there an association between invasive lobular carcinoma of the breast and a family history of gastric cancer?

et al. 2015

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CDH1 gene mutations have been found to be associated with diffuse type gastric cancer and invasive lobular carcinoma (ILC) of the breast. To the best of our knowledge, this is the only study relating a family history of gastric cancer to ILC of the breast. We conducted a retrospective study comparing the family history of malignancies in patients with invasive ductal carcinoma (IDC) of the breast and ILC treated in our Medical Center. The comparison was evaluated in both types of breast cancer groups, dividing the patients into two age groups, <50 and ≥50 years. One thousand one hundred and sixty-seven patients with IDC and ILC entered the study. A family history of malignancies was reported in 21.6 % of patients with IDC as opposed to 37.8 % of patients with ILC (P < 0.001). A history of gastric cancer was reported in 7.2 % in the ILC group as compared to 2.3 % in the IDC group, P < 0.008. A family history of breast cancer was more common in the ILC group as opposed to the IDC group, 18 versus 8.1 % respectively, P = 0.002 and persisted in both age groups. We conclude that a family history of malignancies in first degree relatives is more common in patients with ILC than IDC and that there is a significant association between a family history of gastric cancer and ILC.

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Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1

Cited by 75 publications

References 63 publications

Hereditary diffuse gastric cancer in two families: A case report

Hereditary diffuse gastric cancer in two families: A case report

Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer

Is there an association between invasive lobular carcinoma of the breast and a family history of gastric cancer?

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