The germline CDH1 c.48 G>C substitution contributes to cancer predisposition through generation of a pro-invasive mutation

• Published in: Mutation research Vol. 770; p. 106
• Main Authors: Zhang, Liying, Xiao, Alexander, Ruggeri, Jeanine, Bacares, Ruben, Somar, Joshua, Melo, Soraia, Figueiredo, Joana, Simões-Correia, Joana, Seruca, Raquel, Shah, Manish A
• Format: Journal Article
• Language: English
• Published: Netherlands 01-12-2014
• Subjects: Amino Acid Substitution; Animals; Cadherins - genetics; CHO Cells; Cricetinae; Cricetulus; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Glutamic Acid - genetics; Histidine - genetics; Humans; Neoplasm Invasiveness - genetics; Pedigree; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Young Adult; Hereditary gastric cancer; Missense mutation; CDH1; Invasion
• ISSN: 1873-135X
• DOI: 10.1016/j.mrfmmm.2014.10.001

Mutation screening of CDH1 is a standard of care for patients who meet criteria for Hereditary Diffuse Gastric Cancer (HDGC). In this setting, the classification of the sequence variants found in CDH1 is a critical step for risk management of patients with HDGC. In this report, we describe a germline CDH1 c.48 G>C variant found in a 21 year old woman and her living great uncle, who were both diagnosed with gastric cancer and belong to a family with high incidence of this type of cancer. This variant occurs at the last nucleotide of exon 1 and presumably results in a Gln-to-His change at codon 16 (Q16H). We used cloning strategies to evaluate the effects on mRNA stability and found that 5/27 and 0/17 clones have the "C" mutant allele in patient and her great uncle, respectively. In vitro functional studies revealed that the germline missense mutant (Q16H) had a pro-invasive cell behavior. Both results (functional and clinical) support the conclusion that the CDH1 c.48 G>C (Q16H) variant contributes to HDGC through the generation of a pathogenic missense mutation with loss of anti-invasive function.