Original Singularity Network Gastric cancer is the fifth most common cancer in the world and the third most common cause of cancer death. It is particularly common in East Asian populations [1,2]. Although most gastric cancers are sporadic, about 10% of cases show familial aggreg

Original Singularity Network

Gastric cancer is the fifth most common cancer in the world and the third most common cause of cancer death. It is particularly common in East Asian populations [1,2].

Although most gastric cancers are sporadic, about 10% of cases show familial aggregation. According to existing reports, 3% to 5% of gastric cancer cases are related to hereditary gastric cancer susceptibility syndromes, including hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma, proximal gastric polyposis, and familial intestinal type gastric cancer [3,4].

HDGC is considered to be a type of gastric cancer with a genetic tendency. Studies have shown that 25% to 50% of HDGC cases carry CDH1 or CTNNA1ht Germline variation on ml7, but still The genetic mechanism of 50% to 75% of HGDC cases is not clear [5], and the mutation rate of CDH1 in East Asian populations, especially Chinese, is also unknown.

This requires Chinese scientists to solve this problem.

Recently, a research team led by Xu Ruihua and Qiu Miaozhen from Sun Yat-sen University Cancer Center published important research results in the JAMA Network Open journal[6].

They conducted a retrospective cohort analysis and performed whole-exome and targeted sequencing on 284 leukocyte samples and 186 matched tumor samples from 284 HDGC patients and found that The germline mutation rate of CDH1 in Chinese HDGC patients is only 2.8%, while the somatic mutation mutation rate is 25.3%.

They also found that some genes with higher germline mutation rates in Chinese HDGC patients were not consistent with previously reported genes, and that there may be an interaction between genetic and environmental factors in the pathogenesis of Chinese HDGC patients.

Screenshot of the paper

Xu Ruihua’s team reviewed the period from January 1, 2002 to August 31, 2018 Between days, 10,431 patients diagnosed with gastric cancer at the Sun Yat-sen University Cancer Center were retrospectively analyzed. The number of HDGC cases finally included in the analysis was 284 (two HDGC patients were from Foshan First People's Hospital).

Most of these 284 HDGC patients were stage III or IV patients (190 cases, 66.9%), and patients who were diagnosed with diffuse gastric cancer before the age of 40 and had no family history (254 cases, 89.4%). The median age of patients at diagnosis was 35 years old, 161 cases (56.7%) were female, and the median follow-up period was 21.7 months. Only 8 (2.8%) patients were infected with EBV, which was much lower than the previously reported EBV infection rate in gastric cancer patients. The 5-year survival rate of patients was 61.4%, which was higher than the 44.1% previously reported for sporadic gastric cancer patients.

Next, the research team performed whole-exome sequencing on the leukocyte samples of 284 HDGC patients and the matched 186 tumor samples. They used sequencing data to identify germline and somatic variants carried by patients.

Based on the detected germline variants, the research team found that only 8 patients in carried variants in CDH1, which was quite different from the results of previous studies, and the variants carried by the patients were all that had not been reported before. This indicates that Chinese HDGC patients have different genetic backgrounds and pathogenic mechanisms.

CDH1 Germline variation and somatic variation

In addition, previous studies have believed that CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, PALB2ht Mutations in ml7, BRCA1, and RAD51C may be related to the susceptibility of CDH1 wild-type HDGC.However, Xu Ruihua's team found that the mutation rate of these genes in Chinese HDGC patients is still low, and the mutations that occurred are inconsistent with previous reports.

In Chinese HDGC patients, the genes with the highest germline mutation rate of are MUC4 (19%), ABCA13 (10%), ZNF469 (10%), FCGBP (10%), IGFN1 (10%), RNF213 (10%) and SSPO (10%), these genes are all unreported . Among them, the gene with the highest mutation rate, MUC4, was mutated in 53 patients. Some studies have pointed out that MUC4 may cause canceration of fibroblasts in mice. Therefore, overexpression of MUC4 may promote the malignancy of gastric cancer through the ERBB2 pathway.

Germline variant mutation spectrum in Chinese HDGC patients

Using paired tumor samples, the research team identified somatic variants in 186 HDGC patients. The gene with the highest mutation rate was TP53 (32.3%) . Interestingly, although the germline mutation rate of CDH1 is not high in Chinese HDGC patients, the somatic mutation rate of is as high as 25.3%. In addition, the research team also found that genes such as HRCT1, KRTAP5-4 are significantly mutated genes (driver genes) in Chinese HDGC patients.

The somatic mutation map of Chinese HDGC patients

Xu Ruihua’s team then compared the Chinese HDGC patients and TCGA sporadic diffuse gastric adenocarcinoma (D-STAD) patients. Cell mutation load, it was found that the gene mutation frequency of the two cohorts was significantly correlated (R=0.24, P2.2×10-16) , but the mutation rate of Chinese HDGC patients was significantly lower than that of D-STAD patients on some genes. For example, the mutation rate of MLLT4 in D-STAD patients was 10%, while it was 0% in Chinese HDGC patients. The

research team also compared the frequency of somatic mutations in the two cohorts on pathways that play an important role in the occurrence and development of gastric cancer such as PI3K-Akt, MAPK, Wnt and TGF-β, and found that the frequency of mutations in D-STAD patients was higher than that in Chinese HDGC patients.

On the basis of somatic variation, the research team also analyzed the copy number variation in HDGC patients, and they found 6p22.2 and 9p13.2 is a high-frequency amplification region, while q21.2 and 0q21.3 are high-frequency deletion regions. Specifically at the gene level, the genes with higher copy number variation frequencies are PTK6 (44.6%), ERBB3 (13.4%), and PIK3CA (11.8%). These three genes are all known oncogenes in gastric cancer.

A region with significantly higher copy number mutation frequency in Chinese HDGC patients

In order to explore the etiology of Chinese HDGC patients, Xu Ruihua's team analyzed the somatic mutation characteristics of all samples and matched them with the mutation characteristics in the COSMIC database. They found three main features, namely (named after COSMIC features): Feature 1 (spontaneous deamination of 5-methylcytosine), Feature 5 (unknown cause), and Feature 24 (aflatoxin exposure). It shows that environmental factors also play a major role in the occurrence of HDGC, and there may be an interaction between genetic and environmental factors.

Finally, Xu Ruihua’s team analyzed the variants related to clinical prognosis.Among the germline variants, they found that has 7 gene variants that are related to overall survival, namely SDK1, HSPG2, FSIP2. CUBN, NCKAP5, FLNB and MUC16.

has a large number of genetic mutations related to overall survival among somatic mutations. Among them, the genes with higher mutation frequency are FGFR3 (HR, 2.2), ASPSCR1 (HR, 2.2), CIC (HR, 2.4), DGCR8 (HR, 2.2), and LZTR1 (HR, 2.5). Pathway enrichment analysis found that these genes were enriched in interferon-related pathways. The

research team also made clinically operable annotations of somatic mutations in Chinese HDGC patients by integrating multiple databases such as OncoKB and CIViC. Finally, 263 single nucleotide variants in 125 patients and 338 copy number variants in 153 patients were annotated as potentially clinically actionable variants.

In general, this retrospective cohort study describes the germline variation characteristics of Chinese HDGC patients for the first time, and illustrates the large differences in germline variation characteristics between Chinese patients and patients analyzed in other previous studies. It also proposes some potentially clinically actionable variation targets in Chinese HDGC patients, which can provide a reference for future research in the field of HDGC.