Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma

Abstract

Objective To reveal the distribution signature of cancer susceptibility genes in patients with gastric adenocarcinoma, offering a diagnostic and prognostic surrogate for disease risk management and therapeutic decisions. Methods A total of 282 patients with gastric adenocarcinoma (182 males and 100 females) were enrolled in this study, with peripheral blood genomic DNA extracted. Mutations of 69 canonical cancer susceptibility genes or presumably tumor-related genes were analyzed by targeted capture-based high-throughput sequencing. Candidate mutations were particularly selected for discussion on tumor pathogenesis according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Results In this study, 7.1% (20/282) of patients with gastric adenocarcinoma were found to harbor mutations of canonical or presumable cancer susceptibility genes. The detection rate in male patients (3.8%, 7/182) was significantly lower than that in female patients (13%, 13/100) (P=0.004). The most recurrent mutations were in A-T mutated ( ATM ) (1.1%, 3/282), followed by BRCA1 , BRIP1 and RAD51D , all showed a detection rate of 0.7% (2/282). Mutations in three genes associated with hereditary gastric cancer syndromes were detected, namely, PMS2 and EPCAM associated with Lynch syndrome and CDH1 associated with hereditary diffuse gastric cancer. The detection frequencies were all 0.4% (1/282). Notwithstanding no significant difference observed, the age of patients with pathogenic mutations or likely pathogenic mutations is slightly younger than that of non-carriers (median age: 58.5 vs . 60.5 years old), while the age of patients with ATM mutations was the youngest overall (median age: 49.3 years old). Conclusions Our study shed more light on the distribution signature and pathogenesis of mutations in gastric cancer susceptibility genes, and found the detection rate of pathogenic and likely pathogenic mutations in male patients was significantly lower than that in female patients. Some known and unidentified mutations were found in gastric cancer, which allowed us to gain more insight into the hereditary gastric cancer syndromes from the molecular perspective.

Hereditary Gastric Cancer: Single-Gene or Multigene Panel Testing? A Mono-Institutional Experience

“…However, we found a statistically significant difference between the detection of PVs in IGCs versus DGCs, suggesting that the MGPT approach may be more advantageous in selected IGCs than in selected DGCs. Interestingly, by comparison with the literature, we also observed a difference between the detection of CDH1 PVs by SGT in our selected GC patients and by MGPT in previously reported unselected patients [23,26]. Therefore, CDH1 genetic testing should preferably be recommended according to specific selection criteria.…”

“…The MGPT evidenced, in addition to the PVs previously identified by SGT, two further PVs in the ATM and RAD51D genes. Contrary to ATM, previously reported as a possible candidate gene for both HDGC and FIGC, RAD51D was detected in only a few cases of GC patients [23]. Interestingly, the ATM PV carrier presented personal and family history strongly consistent with the typical clinical picture associated with this gene, being the patient diagnosed with pancreatic cancer in addition to gastric cancer and having a daughter with early-onset breast cancer.…”

Next-generation universal hereditary cancer screening: implementation of an automated hereditary cancer screening program for patients with advanced cancer undergoing tumor sequencing in a large HMO

“…There is a growing body of literature demonstrating that variants found on tumor DNA sequencing tests for certain high-and moderate-risk hereditary cancer risk genes are also frequently present in the germline. This has been demonstrated in paired germline-tumor tumor DNA analysis from large unselected groups of patients with diverse cancers [3,4] as well as work focused on specific cancer types [10][11][12][13][14]. Both approaches have demonstrated that tumor variants in certain hereditary cancer genes are likely to be present in the germline across a large spectrum of tumor types.…”

Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility

“…Apparently, there is no correlation between the presence of ATM PVs and the onset of a specific gastric cancer histotype as the association with ATM PVs has been described for both diffuseand intestinal-type gastric adenocarcinoma [10]. Recently, in a cohort of 282 Chinese patients with gastric adenocarcinoma tested for germline variants in a panel of 69 cancer susceptibility genes, ATM PVs were the most common, with a prevalence of 1.1% in affected individuals [20]. All identified ATM PVs were truncating (nonsense or frameshift variants) and were associated with a lower age of onset (mean age of 49.3) compared to the age of all other patients with pathogenic variants in other genes (mean age of 58.5) or to patients with no PVs from the same cohort (mean age of 60.5) [20].…”

“…Recently, in a cohort of 282 Chinese patients with gastric adenocarcinoma tested for germline variants in a panel of 69 cancer susceptibility genes, ATM PVs were the most common, with a prevalence of 1.1% in affected individuals [20]. All identified ATM PVs were truncating (nonsense or frameshift variants) and were associated with a lower age of onset (mean age of 49.3) compared to the age of all other patients with pathogenic variants in other genes (mean age of 58.5) or to patients with no PVs from the same cohort (mean age of 60.5) [20]. In comparison, the worldwide median age of onset for gastric cancer is approximately 70 years of age [21].…”