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

Mutation Research
Liying ZhangManish A Shah

Abstract

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.

References

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Jun 5, 2007·JAMA : the Journal of the American Medical Association·Pardeep KaurahDavid Huntsman
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Apr 8, 2010·Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association·Parry GuilfordVanessa Blair
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Aug 25, 2011·Breast Cancer Research and Treatment·Liying ZhangKenneth Offit
May 23, 2012·Biochimica Et Biophysica Acta·Joana ParedesRaquel Seruca

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