Hereditary diffuse gastric cancer: association with lobular breast cancer

Schrader, Kasmintan A.; Masciari, Serena; Boyd, Niki; Wiyrick, Sara J.; Kaurah, Pardeep; Senz, Janine; Burke, Wylie; Lynch, Henry T.; Garber, Judy E.; Huntsman, David G.

doi:10.1007/s10689-007-9172-6

Cited by 123 publications

(76 citation statements)

References 83 publications

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“…24 In view of the increased cancer risk, intensified surveillance programmes are indicated. 22,25 For women with neurofibromatosis type I (NF1) (MIM no. 162200), an autosomal dominant disorder caused by NF1 mutations, a moderately increased breast cancer risk was reported.…”

Section: Breast Cancer-associated Cancer Predisposition Syndromesmentioning

confidence: 99%

Breast cancer susceptibility: current knowledge and implications for genetic counselling

et al. 2008

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Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.

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Section: Breast Cancer-associated Cancer Predisposition Syndromesmentioning

confidence: 99%

Breast cancer susceptibility: current knowledge and implications for genetic counselling

et al. 2008

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“…Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome characterized by a high risk of developing diffuse gastric cancer [1][2][3] and lobular breast cancer [4][5][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.…”

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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“…In almost all resected stomachs of asymptomatic CDH1 mutation carriers multiple foci of signet ring cells (SRCs) were found. [15][16][17] Female carriers are known to have an additional high risk of developing lobular breast cancer (LBC) with LTR of 60% by the age of 80 years, rising from age 40,6,7,[18][19][20][21] whereas other tumor sites like colon and prostate might also be associated with HDGC. 22,23 In The Netherlands, CDH1 mutation analysis is available in a clinical setting since 1998.…”

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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 diffuse gastric cancer: association with lobular breast cancer

Cited by 123 publications

References 83 publications

Breast cancer susceptibility: current knowledge and implications for genetic counselling

Breast cancer susceptibility: current knowledge and implications for genetic counselling

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

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

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