Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer

• Published in: International journal of molecular sciences Vol. 20; no. 20; p. 4980
• Main Authors: Norero, Enrique, Alarcon, M Alejandra, Hakkaart, Christopher, de Mayo, Tomas, Mellado, Cecilia, Garrido, Marcelo, Aguayo, Gloria, Lagos, Marcela, Torres, Javiera, Calvo, Alfonso, Guilford, Parry, Corvalan, Alejandro H
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.10.2019; MDPI
• Subjects: Adult; Age; Alleles; Antigens, CD - genetics; Breast cancer; Cadherins - genetics; cdh1; CDH1 gene; Cell adhesion & migration; Chemotherapy; Clustering; Consortia; Deoxyribonucleic acid; DNA; E-cadherin; Family medical history; Female; Gastrectomy; Gastrectomy - methods; Gastric cancer; Gastrointestinal surgery; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; hdgc; Humans; Laparoscopy; Lymphatic system; Male; Middle Aged; Mutation; Neoplasm Staging; Neoplastic Syndromes, Hereditary - diagnosis; Neoplastic Syndromes, Hereditary - genetics; Neoplastic Syndromes, Hereditary - prevention & control; Nucleotide sequence; Patients; Pedigree; prophylactic gastrectomy; Prophylactic Surgical Procedures; Stomach Neoplasms - diagnosis; Stomach Neoplasms - genetics; Stomach Neoplasms - prevention & control; Tumors; Young Adult; prophylactic gastrectomy; CDH1; HDGC
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20204980

Germline pathogenic variants in the gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize 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 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 ≤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 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>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's sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.