Identification of c.1531C&gt;T Pathogenic Variant in the <i>CDH1</i> Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer

• Main Authors: Enrique Norero, M. Alejandra Alarcon, Christopher Hakkaart, Tomas de Mayo, Cecilia Mellado, Marcelo Garrido, Gloria Aguayo, Marcela Lagos, Javiera Torres, Alfonso Calvo, Parry Guilford, Alejandro H. Corvalan
• Format: Article
• Language: English
• Published: MDPI AG 2019-10-01
• Series: International Journal of Molecular Sciences
• Subjects: hdgc; <i>cdh1</i>; prophylactic gastrectomy
• Online Access: https://www.mdpi.com/1422-0067/20/20/4980

Germline pathogenic variants in the <i>CDH1</i> gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize <i>CDH1</i> mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the <i>CDH1</i> gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at &#8804;50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the <i>CDH1</i> gene: (a) The c.88C&gt;A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C&gt;T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband&#8217;s sister revealed stage I signet-ring cell carcinoma. The finding of 1531C&gt;T pathogenic variant in the <i>CDH1</i> in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in <i>CDH1</i> negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.