E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer

Guilford, Parry; Hopkins, Justin; Grady, William M.; Markowitz, Sanford D.; Willis, Joseph E.; Lynch, Henry T.; Rajput, Ashwani; Wiesner, Georgia L.; Lindor, Noralane M.; Burgart, Lawrence J.; Toro, Tumi; Lee, Don; Limacher, Jean Marc; Shaw, David W.; Findlay, Michael; Reeve, Anthony E.

doi:10.1002/(sici)1098-1004(1999)14:3<249::aid-humu8>3.0.co;2-9

Cited by 257 publications

(124 citation statements)

References 25 publications

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“…[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. 18 Thus, CDH1 satisfies criteria for classification as a tumour supressor gene according to Knudsons 2 hit hypothesis, 19 in cases with somatic and germline mutations in the CDH1 gene.…”

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confidence: 99%

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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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confidence: 99%

“…Mutation screening studies of CDH1 have previously been performed with PCR/SSCP [12][13][14]16 or direct sequencing. 15 We decided to test Denaturing High Performance Liquid Chromatography (DHPLC), a highly sensitive PCR-based technique for nucleotide variant detection.…”

mentioning

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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“…Another family with an extensive unconfirmed history of diffuse gastric cancer (two confirmed cases) carries a p.Q64* mutation (Guilford et al. 1999). …”

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confidence: 99%

“…The penetrance of gastric cancer in people with CDH1 mutations has been estimated to range from 83% to 40%, depending on gender and ethnicity (Guilford et al. 1999; Kaurah et al. 2007; Pharoah et al.…”

Section: Discussionmentioning

confidence: 99%

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Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

Huynh

Laukaitis

2016

Molec Gen & Gen Med

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BackgroundThe reported penetrance of germline CDH1 mutations is high in families with hereditary diffuse gastric cancer (HDGC). Men and women have a 70% and 56%, respectively, cumulative risk of developing diffuse gastric cancer by age 80. Women additionally have a 42% cumulative risk of developing breast cancer. Due to the high penetrance of these mutations, prophylactic total gastrectomy is currently recommended for CDH1 mutation carriers. However, whether everyone with a CDH1 gene mutation is at risk for HDGC is not clear.MethodsMutation identification was performed by next‐generation sequencing. Mutations and variant status was confirmed by Sanger sequencing in 11 family members.ResultsWe present two families with pathogenic CDH1 mutations. The first family carries a novel truncating, nonsense CDH1 mutation that we were able to trace for three generations, but reports no family history of diffuse gastric cancer. The occurrence of cancer in this family deviates significantly from the expectation for HDGC. The proband from the second family presents with breast cancer and carries a previously reported pathogenic CDH1 mutation, but also reports no family history of diffuse gastric cancer.ConclusionsOur study demonstrates the need for further analysis of CDH1 mutation penetrance in order to better counsel asymptomatic CDH1 mutation carriers on preventative measures and general care.

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Germline CDH1 Variants and Lifetime Cancer Risk

Ryan,

Fasaye,

Gallanis

et al. 2024

JAMA

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ImportanceApproximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants.ObjectiveTo describe gastric and breast cancer risk estimates for individuals with CDH1 variants.Design, Setting, and ParticipantsMulticenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022.Main Outcomes and MeasuresHazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years.ResultsA total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%).Conclusions and RelevanceAmong families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.

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E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer

Cited by 257 publications

References 25 publications

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

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

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer

Germline CDH1 Variants and Lifetime Cancer Risk

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