The objective of this study was to determining the frequency of different sub-types of pathogenic CDH1 germline mutations in healthy and asymptomatic individuals from families with the hereditary diffuse gastric cancer (HDGC) syndrome. Relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations. The collected variants were classified according to their subtype into the following classes: missense, non-sense, splicing, insertions and deletions. The χ2 test was used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was statistically significant. CDH1 genetic screening data were retrieved for 224 patients with GC and 289 healthy individuals. Among the subjects that had tested CDH1 positive, splicing mutations were found in 30.4% of the healthy individuals and in 15.2% of the patients with GC (p=0.0076). Missense mutations were also found to occur in healthy subjects with higher frequency (22.2%) than in GC-affected individuals (18.3%), but the difference was not significant in this case. In families meeting the clinical criteria for the HDGC syndrome, CDH1 splicing and missense germline mutations have been reported to occur with higher frequency in healthy subjects than in patients with cancer. This preliminary observation suggests that not all pathogenic CDH1 germline mutations confer the same risk of developing GC.
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Contributors GC conceived, designed and supervised the study. VB carried out the statistical analyses. FM, AMDS, EV and GM performed the bibliographic search and analysed the data. BB performed and/or interpreted the evidence for CDH1 variants classification. GC and VB wrote the manuscript, with relevant input from PV and VG. All authors critically revised the article for important intellectual content.
Funding This manuscript was supported by the Italian Ministry of Health (project title: Understanding how CDH1 germline mutations affect hereditary lobular breast cancer; grant code: GR-2016-02361655).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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