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

Abstract

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.

Facteurs de risque génétiques pour le cancer de la prostate

“…Dans les familles concernées, la recherche de mutations germinales du gène de la cadhérine E, prédisposant à certaines formes familiales de cancer de l'estomac, n'a cependant pas retrouvé d'association avec le cancer de la prostate [19].…”

Characterization of a Recurrent Germ Line Mutation of the E-Cadherin Gene: Implications for Genetic Testing and Clinical Management

“…These included 10 isolated early-onset DGC cases and one case of synchronous DGC and LBC. Two of the families under analysis shared the same germ line change, an exon 7 nonsense mutation previously reported in a Swedish HDGC family (14). We used haplotype analysis on the three families to rule out the possibility of founder mutation.…”

Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour

“…Knowledge regarding the genetic basis of HDGC has greatly increased in the last few years, due to the discovery of germline mutations in the gene coding for E-cadherin (CDH1) within families with this cancer predisposing syndrome (Gayther et al, 1998;Guilford P et al, 1998;Guilford PJ et al, 1999;Iida et al 1999;Keller et al, 1999;Richards et al, 1999;Shinmura et al, 1999;Yoon et al, 1999;Avizienyte et al, 2001;Dussaulx-Garin et al, 2001;Humar et al, 2002;Jonsson et al, 2002;Oliveira et al, 2002;Yabuta et al, 2002;Wang et al, 2003).…”