Abstract
Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer (HDGC) and have been identified in multiple ethnicities. However, CDH1 germline mutations have seldom been documented in Chinese patients with HDGC, and their frequency remains unclear. Here, we aimed to examine the frequency of CDH1 germline mutations in Chinese patients with HDGC. In total, 285 patients who met the International Gastric Cancer Linkage Consortium 2015 testing criteria of HDGC for CDH1 germline mutations were recruited. All 16 CDH1 exons, including neighboring intronic sequences, were amplified using polymerase chain reaction and screened using Sanger sequencing. Variants were analyzed using Mutation Surveyor V4.0, SIFT, and PolyPhen-2 software. Three nonsense and nine missense CDH1 germline mutations were identified in 21 of 285 index cases (7.4%). Two CDH1 germline mutations, N405Y (Asn405Tyr) and W409X (Trp409Ter), were identified as new variants. In addition, up to 28.6% of CDH1 mutations in the 21 indicated patients were identified as c.1775G>C (E551Q). The frequency of CDH1 mutations was 6.5% (7/108) in HDGC and 7.9% (14/177) in early onset diffuse gastric cancer (EODGC). The mutation detection rates of CDH1 in males and females were 6.7% (4/60) and 8.5% (10/117) in EODGC and 4.6% (3/65) and 9.3% (4/43) in HDGC, respectively. These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese.
Highlights
Gastric cancer (GC) is considered the fifth most common malignancy (Torre et al 2015) and the third leading cause of cancer-related deaths worldwide (Ferlay et al 2013)
The mutation detection rate of CDH1 in males and females was 6.7% (4/60) and 8.5% (10/117) in early onset diffuse gastric cancer (EODGC) and 4.6% (3/65) and 9.3% (4/43) in hereditary diffuse gastric cancer (HDGC), respectively. These data reveal, for the first time, the type and frequency of CDH1 germline mutations in Chinese HDGC, and demonstrate that germline CDH1 mutations are a noteworthy contributor to the high frequency of HDGC in Chinese
HDGC can be caused by heterozygous germline mutations in CDH1, which are regarded as the major genetic cause of HDGC (Guilford et al 1998)
Summary
Gastric cancer (GC) is considered the fifth most common malignancy (Torre et al 2015) and the third leading cause of cancer-related deaths worldwide (Ferlay et al 2013). HDGC can be caused by heterozygous germline mutations in CDH1, which are regarded as the major genetic cause of HDGC (Guilford et al 1998). More than 100 different germline CDH1 mutations have been reported in various ethnicities worldwide (Hansford et al 2015). These germline mutations are dispersed throughout the CDH1 gene, and no mutations have been described for HDGC
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