Complementary molecular approaches reveal heterogeneous CDH1 germline defects in Italian patients with hereditary diffuse gastric cancer (HDGC) syndrome. Issue 5 (3rd February 2014)

• Record Type: Journal Article
• Authors: Molinaro, Valeria; Pensotti, Valeria; Marabelli, Monica; Feroce, Irene; Barile, Monica; Pozzi, Simonetta; Laghi, Luigi; Serrano, Davide; Bernard, Loris; Bonanni, Bernardo; Ranzani, Guglielmina Nadia
• Is Part Of: Genes, chromosomes & cancer. Volume 53:Issue 5(2014:May)
• Page Start: 432
• Page End: 445
• Publication Date: 2014-02-03
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22155
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Germline inactivation of the E‐cadherin gene (<italic>CDH1</italic>) is associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant syndrome predisposing to both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). We searched for <italic>CDH1</italic> germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives. We used a series of molecular methods, including: DNA sequencing, multiplex ligation‐dependent probe amplification, single‐nucleotide primer extension, bisulfite sequencing, reverse‐transcription PCR, and bioinformatics tools. We identified pathogenic mutations in 6 out of 32 probands (19%): one truncating and two missense mutations, one large deletion, one allelic expression imbalance and one splicing defect. Three out of six <italic>CDH1</italic> constitutive alterations were novel. Our data support the need for a multimethod approach for <italic>CDH1</italic> genetic testing, demonstrating that both DNA and RNA analyses are required to increase the detection rate of pathogenic mutations, thus reducing the number of patients without a clear molecular diagnosis. On the whole, our results indicate that not only DGC patients, but also subjects with personal or family history of LBC might benefit from <italic>CDH1</italic> genetic testing. Moreover, our findings support the notion that prophylactic gastrectomy should be offered to asymptomatic <italic>CDH1</italic> mutation carriers; indeed, while endoscopic analysis with histological examination of random gastric biopsies can miss cancer foci, gastrectomy performed in these subjects always revealed foci of cancer cells. © 2014 Wiley Periodicals, Inc.</p> </abstract>