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

Enrique Norero,Gloria Aguayo,Parry Guilford,Christopher Hakkaart,Javiera Torres,Marcela Lagos,Alejandro H Corvalan,Marcelo Garrido,Cecilia Mellado,Tomas De Mayo,M Alejandra Alarcon,Alfonso Calvo

doi:10.3390/ijms20204980

Abstract

Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 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 CDH1 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 CDH1 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 CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.

Highlights

Gastric cancer (GC) is the fifth most common cancer, with more than 1,033,000 new cases every year, and the third leading cause of cancer-related death worldwide [1]
We identified the non-synonymous c.1531C>T mutation in the CDH1 gene as a novel germline mutation of hereditary diffuse gastric cancer (HDGC) in the proband case, as well as in five family members
There were 13 patients with family history of diffuse gastric cancer (DGC) in first or second-degree family members, with one ≤ 50 years; 13 probands had three or more family members with DGC at any age; and 27 patients had a diagnosis of DGC ≤ 50 years

Summary

Introduction

Gastric cancer (GC) is the fifth most common cancer, with more than 1,033,000 new cases every year, and the third leading cause of cancer-related death worldwide [1]. In 1964, Jones described a multigenerational New Zealand Maori family with an extremely high incidence of GC and speculated about a genetic role [3]. In 1998, Guilford made the first association between familial GC and a germline mutation in the CDH1 gene in three Maori families [4]. In these patients, a clinical entity called hereditary diffuse gastric cancer (HDGC) has been described [5,6]. HDGC is an autosomal dominant cancer syndrome primarily characterized by an extreme risk of developing diffuse-type GC from a relatively young age [5,7]. More than 120 pathogenic CDH1 variants have been reported across all coding regions of the CDH1 gene [10,12]

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