Although familial aggregation is found in about 10% of GC cases [25], the incidence of CDH1 alterations in patients with or without family history of GC is unclear. We explored CDH1 alterations with NGS and investigated the association with family history in 993 GC patients. We found that occurrence of CDH1 mutation was not significantly associated with family history.
After the first report of germline CDH1 mutation in GC [37], various types of CDH1 mutations have been reported in HDGC or diffuse type GC by polymerase chain reaction and sequencing [3–7] aided with multiplex ligation-dependent probe amplification [8–11] or high-resolution melting analyses [30] from patients with FGC, HDGC, or EOGC. CDH1 germline mutations were identified in 10% of FGC cases[10, 11], 0 ~ 19% of HDGC cases [3–5, 8] and 0 ~ 8.9% [5–7, 9] of EOGC cases [6], as well as in 1.7% of patients with sporadic GC [12]. With NGS, somatic mutations of CDH1 are found in 9%~36% of GC cases[16–22] and are highly prevalent in sporadic EODGC (53.2% of cases). Somatic CDH1 mutation has also been suggested as a poor prognostic marker in diffuse-type GC [17, 22, 23]. The previously reported germline and somatic CDH1 mutations detected in patients with gastric cancer by various technologies are summarized in Table 4. Although a few studies have investigated the frequency and impact of CDH1 mutations in HDGC and EODGC [9, 10, 17, 24], the incidence of CDH1 mutations in sporadic GC patients with or without family history is unclear [25]. To the best of our knowledge, this is the first study exploring CDH1 mutations in association with family history. Our results showed that CDH1 mutations are not influenced by family history.
Table 4
CDH1 mutations found in patients with gastric cancer
Mutation Type | Number of samples | Country | History | Method | Frequency | References |
Somatic | 32 | Chinese | Signet-ring cell carcinoma: sporadic | WGS | 15.60% | [16] |
Somatic | 109 EOGC 115LOGC | Korean | DGC | WES/RNA sequencing | early 53.2%, late 36.0% | [17] |
Somatic | 200 | Hong Kong | 100 pairs of GC | WGS | 10% | [18] |
Somatic | 87 | Japan | DGC | WES | 32% | [19] |
Somatic | 22 | Hong Kong | GC | WES | 9% | [20] |
Somatic | 295 | TCGA data | GC | WES/RNA sequencing | 11% | [21] |
Sporadic | 544 | Chinese | DGC | Targeted sequencing | 11.60% | [22] |
Germline | 499 families, 578 individuals | Netherlands | HDGC | PCR, Sanger sequencing | HDGC, 13.5% | [3] |
Germline | 183 | Portugal | HDGC | Cancer panel, MLPA | 19% | [8] |
Germline | 25 EODGC 23 HDGC | Korean | EODGC HDGC | PCR, MLPA | EODGC, 8% (2 cases) HDGC, 4.3% (1 case) | [9] |
Germline | 236 GC: 175 sporadic, 61 hereditary, 240 cancer free | Chinese | Sporadic | PCR, HRM analysis | 1.70% | [12] |
Germline | 22 | Italy | EOGC | Direct sequencing | 8.90% | [6] |
Germline | 86 | Poland | HDGC | Sanger sequencing | 0 | [4] |
Germline | HDGC 9 EODGC 16 | Portuguese | HDGC EOGC | PCR-SSCP | HDGC, 11.1% (1 case) EODGC − 0 | [5] |
Germline | 66 | North America | EOGC | PCR-SSCP | 7.60% | [7] |
Germline | 6 families, 19 patients | Korean | FDGC | PCR-SSCP | 10.06% | [10] |
Germline | 6 families, 30 patients | Caucasian | FGC | PCR-SSCP | 10% | [11] |
GC gastric cancer, DGC diffuse gastric cancer, HDGC hereditary diffuse gastric cancer, EODGC early-onset diffuse gastric cancer, EOGC early-onset gastric cancer, LOGC late-onset gastric cancer, FGC familial gastric cancer, WGS whole genome sequencing, WES whole exome sequencing, PCR polymerase chain reaction, MLPA multiplex ligation-dependent probe amplification, SSCP single-strand conformation polymorphism |
In the present study, we identified 146 CDH1 mutations in 993 patients. Eight CDH1 mutations were germline (0.8%, 8/993), and this incidence is similar to a previous study in a Chinese population (1.7%, 4/236), the only study investigating CDH1 germline mutation in sporadic GC patients [12]. In previous studies in EODGC patients, CDH1 germline mutation rates were higher in Korean (8%, 2/25) [9] and Italian populations (7.2%, 19/264) [6]. In a meta-analyses study, GC occurring in a high-prevalence area harbored less frequent CDH1 germline mutations than that in a low-incidence area [2]. Based on these observations, our low incidence of CDH1 germline mutations may be due to patient age (more frequent CDH1 germline mutations in younger patients) and because the present study was performed in a GC-prevalent area.
In GC-prevalent areas, the ratio of missense mutations was higher than that of non-missense (deletion, insertion, truncating, and nonsense) mutations [2]. In addition, non-missense mutations were reported to be likely pathogenic compared with missense mutations. We also found that the frequency of missense mutation was higher (67.8%) compared with that of non-missense mutation, and this result is similar to the previous analysis. A recent comprehensive genomic study demonstrated that RhoGAP domain-containing fusions or PPAPDC1A fusions, which are mostly somatic mutations, are common in GC of diffuse-type [38]. In addition, germline mutations in genes such as CTNNA1 were observed at a similar frequency as CDH1 germline mutation [39]. These findings suggest that GC might be frequently caused by somatic mutations rather than germline alterations of CDH1 in GC-prevalent areas such as Korea, as previously suggested [2].
Unlike previous studies that focused exclusively on HDGC patients, we compared the distribution of CDH1 alterations in patients with and without family history of GC. As a result, most CDH1 alterations in both groups were somatic mutations. Thus, CDH1 somatic mutation appears to play a more important role than germline mutation regardless of family history;
The limitation of this study is that the patient's family history was investigated only through electronic medical records. Therefore, the age of onset and histological information of GC in the patient's family could not be accurately identified. In addition, there is a possibility of missed records. Further studies might be required to analyze the family information about GC more in detail with pedigree analysis.