Figures
↓ Figure 1. Cumulative risk of gastric cancer in individuals up to 80 years of age according to family hereditary breast and ovarian cancer (HBOC) statuses. The cumulative risks of gastric cancer were estimated for men and women who underwent National Cancer Genome profiling. *P < 0.001, **Not significant.
↓ Figure 2. Comparison of gastric tissue samples. Compared to male Gan mice, female Gan mice showed fewer inflammatory and highly dysplastic (adenocarcinoma) cells in their gastric mucus tissues. (a) Panels 1 and 4 show the pathological findings of normal gastric mucosal tissue from a C57BLACK/6 wild-type mouse. Genetically engineered Gan mice exhibit to spontaneously develop gastritis and gastric cancer (panels E2, E3, E5, E6). Compared to the gastric mucosal tissue of male Gan mice of the same age (E5, E6), the gastric mucosal tissue of female Gan mice clearly had fewer atypical and highly atypical cells (E2, E3). (b) Only a few inflammatory cells were observed in the gastric mucosal tissues of 8-month-old Gan mice (panels: E11, E12). However, many inflammatory cells were observed in the mucosal tissues of 12-month-old female Gan mice (panels E12, E13). Scale bar: 100 mm.
↓ Figure 3. BRCA2 is induced by estrogen stimulation. (a) We investigated whether pathogenic mutations in the BRCA2 gene result in genetic instability that can ultimately lead to breast and ovarian cancer induction by estrogen. BRCA2 protein expression was induced in an estrogen concentration-dependent manner in cultured gastric adenocarcinoma cells (AGS cells and MKN28 cells). (b) Schematic representing BRCA2 gene expression induced by estrogen stimulation. Notably, no induction of BRCA2 protein was observed in progesterone-stimulated MCF7 and HeLa cells. (c) Pathological analysis was performed on the gastric tissues of mice carrying certain genetic modifications that were sacrificed at 14 months of age. Based on evidence obtained from our reserch that estrogen-induced BRCA2 may protect against tumor development in the mucosal epithelium of female Gan mice, we investigated the incidence of gastric cancer in C57BL/6, Gan, and Gan BRCA2 mice. No dysplastic cells were detected in the gastric mucosa of normal male and female C57BL/6 mice. Therefore, for female C57BL/6 mice (ovariectomized mice), the number of mice in which only cells exhibiting mild. The asterisk: However, in the gastric mucosa of female C57BL/6-ovariectomy mice in which the estrogen-secreting ovaries had been removed, only low-grade dysplastic cells were observed; neither high-grade dysplastic cells nor cancer cells were detected, therefore, for female C57BL/6 mice (ovariectomized mice), the number of mice in which only cells exhibiting mild dysplasia were observed in the gastric mucosa is reported.
↓ Figure 4. The value of BRCA2 expression status as a prognosis marker. (a) We examined the expression status of BRCA2 in normal gastric mucosal tissue (407 cases) and gastric cancer mucosal tissue (346 cases) using immunohistochemical staining. BRCA2 expression was high in normal gastric mucosal tissue but weak or negative in the mucosal tissue of many gastric cancers. Scale bar: 30 mm. (b) The Mantle 2 color imaging system was used to quantify the expression intensity of BRCA2 in various gastric mucosal tissues. A scatter plot of BRCA2 expression levels revealed a cutoff value of 3.0 to separate high- versus low-expression groups. (c) Patients with gastric cancer were divided into two groups based on BRCA2 expression levels in their resected gastric mucosal tissue: low-BRCA22 (235 cases) and high-BRCA2 expression (111 cases). Kaplan–Meier survival curves revealed longer survival rates in the high-BRCA2 group than in the low BRCA2 group. (d) The median overall survival rates (50%) were 2.1 and 3.7 years in the BRCA2 low and BRCA2 high groups. The 5-year survival rates in the BRCA2 low and BRCA2 high groups were 34.2% and 41.2%. Please refer to Supplementary Material 7 (wjon.elmerpub.com) for details regarding the gastric cancer stage and other information for each patient who participated in this clinical study. F/M/total cases: female cases/male cases/total cases.
Table
↓ Table 1. GC Incidence in Patients From Families With HBOC Based on Genetic Testinga
| Demographic | HBOC families (n = 183) | Non-HBOC families (n = 189) |
|---|
| aGenetic testing: BRACAnalysis Diagnostic System (Myriad Genetics G.K., Zurich, Switzerland). bOther tumors: HBOC-related cancers, i.e., breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer. GC: gastric cancer; HBOC: hereditary breast and ovarian cancer. |
| Overall GC incidence | | |
| Total GC patients (with other tumorsb) | 173 (779) | 41 (205) |
| Total patients evaluated | 4,847 | 4,755 |
| GC incidence (%) | 3.57% | 0.86% |
| Sex distribution of GC patients | (n = 173) | (n = 41) |
| Male GC patients (n) | 129 | 22 |
| Proportion of males (%) | 74.57% | 53.67% |