Diffuse Type Gastric and Lobular Breast Carcinoma in a Familial Gastric Cancer Patient with an E-Cadherin Germline Mutation

Keller, Gisela; Vogelsang, H.; Becker, Ingrid; Hutter, Jörg; Ott, Katja; Candidus, Sonja; Grundei, T.; Becker, Karl‐Friedrich; Mueller, James; Siewert, J. R.; Höfler, Heinz

doi:10.1016/s0002-9440(10)65129-2

Cited by 261 publications

(161 citation statements)

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“…Lack of E-CD expression in one case of familial diffuse type of gastric carcinoma has been reported by Keller et al 25 to be genetically correlating with a case of diffuse ILC in the patients' mother, as a result of a germline mutation in CDH 1 gene. In our study, most of the familial cases had breast or ovarian cancers in their relatives.…”

Section: Discussionmentioning

confidence: 75%

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Chintamani

Rekhi

Bansal

et al. 2010

Indian J Surg Oncol

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Context E-cadherin (E-CD) is an important cell adhesion molecule in normal epithelial cells and has been shown to be an invasion tumor suppressor gene. Materials and methods Various clinicopathological parameters like age, family history, tumor stage, histological grade, lymph node status and other biological markers were also analyzed. Present study reveals E-CD expression in 65 cases of breast cancer including 41 (63%) cases of pure infiltrating ductal carcinoma (IDC), 11 (16.9%) of pure infiltrating lobular carcinoma (ILC); another 10 (15.3%) of mixed ductal/lobular type, and remaining 3 (4.6%) miscellaneous types.Results Negative E-CD expression was noticed more in advancing age groups (P = 0.01). About 59.2% cases showing negative E-CD expression had family history of breast and/or other cancers. E-CD expression was found significantly higher in cases of pure IDC (55.5%) than in pure ILC cases (18.1%) (P = 0.04). Eleven (68.7%) of the total 16 high-grade IDC cases, revealed negative expression. Both cases of comedo carcinoma revealed negative expression. Three (30%) out of 10 mixed cases revealed negative expression in both ductal and lobular areas, while in remaining 7 cases, positvity was seen in ductal areas only. Invasive cribriform and medullary carcinoma revealed a stronger expression, while negative staining was observed in sweat gland carcinoma. E-CD re-expression was noticed in lymph node tumor deposits. A direct association of E-CD expression with ER expression and an inverse association with that of p53 were also observed (P = 0.001), (P = 0.04). Conclusions E-CD expression is useful, but limited, in differentiating IDCs from ILCS. Its negative expression correlates with certain poor prognostic parameters reflecting its use as a marker for invasive cancers. It re-expresses at metastatic sites.

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Section: Discussionmentioning

confidence: 75%

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Chintamani

Rekhi

Bansal

et al. 2010

Indian J Surg Oncol

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“…Several groups have reported germline mutations in families with early onset diffuse gastric cancer. [12][13][14][15][16][17] Individuals in hereditary diffuse gastric cancer (HDGC) families have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. 13,14,16 Recently, it was shown in 2 kindreds with HDGC that they either had the promoter methylated or that they had rendered a somatic mutation in the retained wild-type allele.…”

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confidence: 99%

“…15 We decided to test Denaturing High Performance Liquid Chromatography (DHPLC), a highly sensitive PCR-based technique for nucleotide variant detection. 23 It relies on the principle of heteroduplex analysis by ion-pair, reverse phase liquid chromatography under partially denaturing conditions.…”

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confidence: 99%

Germline mutations in E‐cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer

Jonsson

Bergh

Stattin

et al. 2002

Intl Journal of Cancer

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Somatic mutations in the E-cadherin (CDH1) gene have frequently been reported in cases with diffuse gastric and lobular breast cancers. Recently, germline mutations have been identified in families with diffuse gastric cancers. In families with hereditary prostate cancer (HPC), a significant association of prostate cancer, gastric and/or breast cancer has been observed in epidemiological studies. The aim of this study was to investigate if germline mutations in CDH1 could explain the risk for cancer in HPC families with an excess of gastric and breast cancer. In total, 17 members from 13 HPC families and 3 members from 3 families with hereditary gastric cancer (HGC) were screened for germline CDH1 sequence alterations using PCR/Denaturing HPLC for initial screening of nucleotide variants followed by confirmatory direct sequencing analysis. The frequency of identified novel germline mutations were tested for in 136 cases with hereditary prostate cancer and 215 cases of sporadic prostate cancer with 422 age matched controls in an allelic discrimination assay. In total, 8 sequence variants were detected in 20 samples tested. In the HPC families, we found 2 missense mutations, A592T in exon 12 and a novel D777N in exon 15 and a mutation in intron 5, 687؉92T>A. A previously known polymorphism in exon 13 and 3 sequence variations in introns and untranslated regions were also found, of which the significance is unknown. In HGC-023 with early onset diffuse gastric cancer a truncating mutation, R335X, was identified in exon 7. None of the missense mutations or 687؉92T>A were found in the extended HPC material or in the sporadic prostate cancer cases with age-matched controls in the allelic discrimination assay. We found several germline mutations of unknown clinical significance in the CDH1 gene that probably do not explain the association of prostate, gastric and/or breast cancers in the HPC-families. Two missense mutations and a mutation in intron 5 were identified that do not influence the risk of hereditary or sporadic prostate cancer in general and are considered to be pedigree specific. In a family with hereditary gastric cancer of the diffuse type, we identified the first truncating germline mutation in a Scandinavian family.

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“…Speci®cally, germline inactivating mutations in the Ecadherin gene have been found in a number of families with inherited predisposition to gastric carcinoma, particularly those with di use type histology (Gayther et al, 1998;Guilford et al, 1998). In one such family, there also appears to be predisposition to breast carcinoma of the lobular type (Keller et al, 1999).…”

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confidence: 99%

Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements

1999

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Inactivation of the E-cadherin cell adhesion molecule is believed critical in the development and behavior of many epithelial cancers, though mutations in the E-cadherin gene account for inactivation in only a fraction of cases. In many breast cancer lines, E-cadherin transcription is extinguished, but the role and signi®cance of alterations in trans-acting transcription factors, promoter hypermethylation, and chromatin changes remain unresolved. To gain further insights into mechanisms underlying Ecadherin inactivation in breast cancer, we analysed somatic cell hybrids resulting from pairwise fusions between breast cancer lines with intact E-cadherin transcription (E-cad+) and lines lacking E-cadherin transcription (E-cad7). All hybrid lines failed to express E-cadherin transcripts and protein, despite the fact that E-cadherin alleles from E-cad+ lines were present in the hybrids. Elements in the proximal 108 bp of the Ecadherin promoter, when present in reporter gene constructs, were su cient to direct strong transcription in E-cad+ breast lines, but displayed weak activity in Ecad7 parental lines and hybrids. E-cadherin expression could not be restored in E-cad7 lines or hybrids by treatment with a DNA demethylating agent and/or a histone deacetylase inhibitor. Our ®ndings suggest loss of E-cadherin expression in some breast cancers may be due to dominant repression of the trans-acting pathways that regulate E-cadherin transcription.

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Diffuse Type Gastric and Lobular Breast Carcinoma in a Familial Gastric Cancer Patient with an E-Cadherin Germline Mutation

Cited by 261 publications

References 15 publications

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Expression of E-Cadherin in breast carcinomas and its association with other biological markers — a prospective study

Germline mutations in E‐cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer

Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements

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