Germline mutations and polymorphic variants in MMR, E‐cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China

Zhang, Yuanying; Liu, Xiaorong; Fan, Yida; Ding, Jiannan; Xu, Aidong; Zhou, Xuefu; Hu, Xu; Zhu, Ming; Zhang, Xiaomei; Li, Suping; Wu, Jianzhong; Cao, Hongyan; Li, Jintian; Wang, Yaping

doi:10.1002/ijc.22206

Cited by 60 publications

(39 citation statements)

References 31 publications

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“…Gastric cancer is a component in several cancer syndromes, of which HNPCC, a dominant disease, is the most common (Lynch and de la Chapelle, 2003;Zhang et al, 2006). The most common cancer site in HNPCC is the colorectum, which showed a borderline increase among siblings in the present study.…”

Section: Discussionsupporting

confidence: 41%

“…Familial clustering of Barrett's oesophagus has been described (Crabb et al, 1985;Jochem et al, 1992), suggesting that the hereditary components for Barrett's oesophagus could be related to both cardia and oesophageal adenocarcinomas. Other factors, either genetic or environmental, may be also related to the family aggregations of cardia cancer (Chow et al, 1998;Zhang et al, 2006). The histological classification used by the Swedish Cancer Registry does not specify intestinal and diffuse types of the Lauren classification and we were thus unable to contribute to the existing literature (Lehtola, 1978;Palli et al, 1994;Lissowska et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

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Familial risk for gastric carcinoma: an updated study from Sweden

Hemminki

Sundquist

2007

Br J Cancer

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Reliable data on familial risks are important for clinical counselling and cancer genetics. However, the estimates of familial risk of gastric cancer vary widely. We examined the risk of familial gastric cancer using the updated Swedish Family-Cancer Database with 5358 patients among offspring and 36 486 patients among parents. There were 133 families with one parent and one offspring diagnosed with gastric cancer, and 20 families with two affected offspring. Familial standardised incidence ratios (SIRs) were 1.63 and 2.93 when parents and siblings presented with gastric cancer, respectively. The high sibling risk was owing to cancer in the corpus (SIR 7.28). The SIR for cardia cancer was 1.54 when parents were diagnosed with any gastric cancer. Cardia cancer associated with oesophageal cancer, particularly with oesophageal adenocarcinoma. Among specific histologies, signet ring cancer showed an increase. A few associations were noted for discordant sites, including the urinary bladder and the endometrium. H. pylori infection, although not measured in the present study, is probably an important risk factor for the high sibling risk of corpus cancer. Familial clustering of cardia cancer is independent of H. pylori infection, and may have a genetic basis. The familial association of cardia cancer with oesophageal adenocarcinoma may provide aetiological clues.

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Section: Discussionsupporting

confidence: 41%

Section: Discussionmentioning

confidence: 99%

Familial risk for gastric carcinoma: an updated study from Sweden

Hemminki

Sundquist

2007

Br J Cancer

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“…E-cadherin mutants T340A, A634V, R749W, E757K, E781D, P799R and V832M found in the HDGC context, 16,18,19,21,[34][35][36][37][38] were constructed by site-directed mutagenesis in the entry vector CDH1pENTR 221 (Clone ID: IOH46767, Invitrogen, Grand Island, NY, USA), following the protocol described by Wang and Wilkinson. 41 By LR recombination reaction, the open reading frame was subcloned in the pEF6/Myc-His vector (Invitrogen).…”

Section: Plasmids Constructionmentioning

confidence: 99%

“…We selected a panel of seven HDGC missense mutations (five intracellular and two extracellular) that have been proven to be pathogenic, 16,18,19,21,[34][35][36][37][38] and studied the ability of the mutant proteins to interact with direct E-cadherin binding partners using proximity ligation assays (PLA), a new tool to detect in situ proteinprotein interactions. 39,40 Fundamentally, PLA is a method where protein-recognition events are converted into detectable DNA molecules.…”

Section: Introductionmentioning

confidence: 99%

The importance of E-cadherin binding partners to evaluate the pathogenicity of E-cadherin missense mutations associated to HDGC

et al. 2012

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In hereditary diffuse gastric cancer (HDGC), CDH1 germline gene alterations are causative events in 30% of the cases. In 20% of HDGC families, CDH1 germline mutations are of the missense type and the mutation carriers constitute a problem in terms of genetic counseling and surveillance. To access the pathogenic relevance of missense mutations, we have previously developed an in vitro method to functionally characterize them. Pathogenic E-cadherin missense mutants fail to aggregate and become more invasive, in comparison with cells expressing the wild-type (WT) protein. Herein, our aim was to develop a complementary method to unravel the pathogenic significance of E-cadherin missense mutations. We used cells stably expressing WT E-cadherin and seven HDGC-associated mutations (five intracellular and two extracellular) and studied by proximity ligation assays (PLA) how these mutants bind to fundamental regulators of E-cadherin function and trafficking. We focused our attention on the interaction with: p120, b-catenin, PIPKIc and Hakai. We showed that cytoplasmic E-cadherin mutations affect the interaction of one or more binding partners, compromising the E-cadherin stability at the plasma membrane and likely affecting the adhesion complex competence. In the present work, we demonstrated that the study of the interplay between E-cadherin and its binding partners, using PLA, is an easy, rapid, quantitative and highly reproducible technique that can be applied in routine labs to verify the pathogenicity of E-cadherin missense mutants for HDGC diagnosis, especially those located in the intracellular domain of the protein. Keywords: HDGC; E-cadherin; CDH1 mutations; E-cadherin trafficking; E-cadherin binding partners; diagnostic method INTRODUCTIONHereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome characterized by a high risk of developing diffuse gastric cancer 1-3 and lobular breast cancer 4-6 during life-time. CDH1 germline gene alterations (mutations or deletions), resulting in E-cadherin inactivation, are the only causative events described till now and were identified in approximately 30% of HDGC cases. 2,3,7 To date, 122 different germline mutations have been described in these families, 8 being the majority of them of the nonsense type, leading to alternative premature termination codons. 3 This type of CDH1 mutant transcripts is commonly downregulated by nonsensemediated decay leading to E-cadherin loss of function 9 and these patients are considered high-risk carriers and are counseled to perform prophylactic total gastrectomy. 10 In about 20% of HDGC families, carriers show CDH1 germline missense mutations 11 and, in contrast to truncating mutations, their pathogenic significance is not straightforward, therefore constituting a problem in terms of genetic counseling and surveillance.In 2004, Fitzgerald and Caldas 10 suggested that the significance of CDH1 missense mutations should be assessed in at least four affected members within a HDGC family in combination with functional and

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“…But Japanese cancer patients with family histories of colorectal and endometrial carcinoma demonstrate the MSH2 c.1168C>T [38]. The strong correlation with early onset of CRC and gastric cancer was found at Chinese population [39,40]. Chinese patients suffering from Lynch syndrome demonstrate the MSH2 c.1168C>T substitution with 4% frequency [41].…”

Section: Discussionmentioning

confidence: 98%