Hereditary diffuse gastric cancer and E-cadherin: Description of the first germline mutation in an Italian family

Roviello, Franco; Corso, Giovanni; Pedrazzani, Corrado; Marrelli, Daniele; Falco, Giulia De; Berardi, Anna; Garosi, Lorenzo; Suriano, Gianpaolo; Vindigni, Carla; Stefano, Alfonso De; Leoncini, Lorenzo; Seruca, Raquel; Pinto, Enrico

doi:10.1016/j.ejso.2006.10.028

Cited by 39 publications

(19 citation statements)

References 13 publications

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“…This is particularly striking taking into account that a well-known ‘familial’ cancer such as breast cancer shows a familial aggregation of only about 12% [20]. In contrast with the high familial aggregation observed, only one deleterious E-cadherin germline mutation was identified even in families fulfilling the HDGC clinical criteria [13, 14]. In keeping with previous reports characterizing regions with a high prevalence of gastric cancer, the observed familial clustering may result from environmental factors and gene-environment interactions rather than autosomal dominant mutations.…”

Section: Discussionmentioning

confidence: 99%

“…One of them, the C1896T mutation, represents a known polymorphism with no proven association to the HDGC syndrome in this family. The C1118T change observed in the second family is a novel missense mutation of pathogenic relevance and it represents the first CDH1 germline mutation described in an Italian family [13]. The data obtained on this family were not sufficient to allow segregation studies, therefore, functional characterization of this alteration has been performed using in silico analysis and in vitro functional assays, as described previously [12, 26], and the pathogenic role of the present mutation has been demonstrated [14].…”

Section: Discussionmentioning

confidence: 99%

“…In 2 of the 14 patients fulfilling the HDGC clinical criteria, E-cadherin germline mutations have been identified [13, 14]. One of them, the C1896T mutation, represents a known polymorphism with no proven association to the HDGC syndrome in this family.…”

Section: Discussionmentioning

confidence: 99%

“…CDH1 germline mutations were first described in three Maori families with autosomal dominant diffuse gastric cancer [11]; since then, additional germline mutations have been identified in families of different ethnic background (European, Japanese, Korean and African-American) [12]. Recently, we have detected the first germline mutation in the CDH1 gene in a family that fulfilled the HDGC criteria [13, 14]. …”

Section: Introductionmentioning

confidence: 99%

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High Incidence of Familial Gastric Cancer in Tuscany, a Region in Italy

et al. 2007

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Objectives: Only 1% of diffuse gastric cancers occur in families with autosomal dominant gastric cancer susceptibility. Germline mutations in the E-cadherin gene account for the hereditary diffuse gastric cancer (HDGC) syndrome. We studied a large cohort of gastric cancer patients from Tuscany, a region in Italy, to evaluate the presence of familial clustering of gastric cancer. Methods: 238 pedigrees were retrospectively studied by structured interviews. All probands with diagnosed gastric cancer were contacted in-person or by phone and tumor types were assessed in first- and second-degree relatives. Familial aggregation was investigated in order to search for families with suspected HDGC. Results: Familial aggregation for gastric cancer was observed in 79 of 238 cases (33.2%). Among these, there were 64 families (81%) with one gastric cancer other than the proband, 10 families with two gastric cancers (12.7%) and 5 families with three gastric cancers (6.3%). Fourteen families fulfilled the HDGC clinical criteria, one of them presenting with a pathogenic germline mutation in the E-cadherin gene (7.1%). Conclusions: The prevalence of familial HDGC appears extremely high. Since only one pathogenic germline mutation was noted in a family fulfilling the HDGC clinical criteria, factors other than E-cadherin gene mutations may contribute to the familial clustering of HDGC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High Incidence of Familial Gastric Cancer in Tuscany, a Region in Italy

et al. 2007

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“…8 Subsequently, different germline mutations have been identified in families with different ethnic backgrounds worldwide. [9][10][11][12][13][14] The lifetime risk (LTR) for GC in HDGC kindreds is high and is estimated >80%. 7 Because of this high risk and the restricted value of current surveillance modalities, prophylactic gastrectomy is recommended as the treatment of choice in CDH1 mutation carriers in preventing advanced GC.…”

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confidence: 99%

CDH1‐related hereditary diffuse gastric cancer syndrome: Clinical variations and implications for counseling

Kluijt¹,

Siemerink

Ausems

et al. 2011

Intl Journal of Cancer

117

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CDH1 mutation carriers have a strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). Clinical data of GC cases and surgical and histological data of prophylactic gastrectomies and mastectomies of all 10 Dutch CDH1 mutation families were collected. In vitro functional assays were performed to analyze the nature of the newly found missense mutation c.1748T>G (p.Leu583Arg). Ten different CDH1 mutations were found. Functional assays gave strong arguments for the pathogenic nature of the p.Leu583Arg mutation. The pedigrees comprised 36 GC cases (mean age 40 years, range 20–72 years) and one LBC case. Twenty‐nine/37 carriers alive, aged 18–61 years, underwent prophylactic gastrectomy. Invasive GC‐foci and premalignant abnormalities were detected in 2 and 25 patients, respectively. In four patients GC/signetring cell (SRC) foci were diagnosed at preoperative gastroscopy. Long‐standing presence of SRCs without progression to invasive carcinoma was shown in two others. Multifocal LBC/LCIS was found in the two prophylactic mastectomy specimens. Clefts of lip and/or palate (CL/P) were reported in seven individuals from three families. The age at onset and aggressiveness of GC is highly variable, which has to be included in counseling on planning prophylactic gastrectomies. The incidence of LBC is expected to increase and prophylactic mastectomy needs to be considered. The relationship between CL/P and CDH1 needs further study to inform future parents from hereditary diffuse gastric cancer (HDGC) families adequately.

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Hereditary Gastric Cancer

Vogelsang

Keller

2008

Hereditary Tumors

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Hereditary diffuse gastric cancer and E-cadherin: Description of the first germline mutation in an Italian family

Cited by 39 publications

References 13 publications

High Incidence of Familial Gastric Cancer in Tuscany, a Region in Italy

High Incidence of Familial Gastric Cancer in Tuscany, a Region in Italy

CDH1‐related hereditary diffuse gastric cancer syndrome: Clinical variations and implications for counseling

Hereditary Gastric Cancer

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