Heterozygous Pathogenic Nonsense ATM Variant Resulting in Unusually High Gastric Cancer Susceptibility

We describe the unusual presentation of familial early-onset gastric cancer due to a heterozygous pathogenic variant in the ATM gene. The proband had gastric cancer (age 45), and reported a sister deceased for diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next Generation Sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, TP53) identified the truncating c.5944C>T, p.(Gln1982*) variant in ATM (NM_000051.3; NP_000042.3) in the proband. The variant segregated in the living affected sister and in the unaffected daughter of the deceased sister. Heterozygous ATM variants appear to significantly increase the risk for pancreatic, breast, gastric and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. Familial gastric cancer is an unusual presentation for ATM. The occurrence of gastric cancer in this family suggests that individual variants may result in different, specific risks. Genotype-phenotype correlations are challenging, given the low penetrance and variable expressivity for ATM variants. Careful family history assessment is pivotal for prevention planning, strengthened by the availability of molecular diagnoses.

The prognostic factors of survival and recurrence in patients with serous ovarian and uterine cancers treated in a single institution for 17 years

Objective: In this study, we aimed to identify the prognostic factors of survival and recurrence in ovarian and uterine serous cancer patients. Materials and methods: This was a retrospective study conducted at Tepecik Research and Education Hospital, İzmir, Turkey, between January 2002 and January 2019. The medical files of 2,027 endometrial and 821 ovarian patients who underwent examination for endometrial cancer and epithelial ovarian cancer were examined retrospectively by the same author. The data of eligible 385 and 49 patients diagnosed with ovarian and uterine serous carcinoma, respectively, were identified for analysis from the hospital database. Descriptive, univariate, and multivariate Cox regression and binary logistic regression analyses of patients were performed. Results: The mean age of ovarian serous cancer patients (n = 385) was 53.9 ± 10.9 years. The mean age of uterine serous cancer patients (n = 49) was 67.2 ± 10.6 years. A total of 81 ovarian serous cancer patients (21.0%) had stage 1, while 24 (6.2%) had stage 2, and 31 (8.1%) had stage 4 disease. A total of 26 uterine serous carcinoma patients (53.1%) had stage 1 disease, 6 (12.2%) had stage 2, 10 (20.4%) had stage 3, and 7 (14.3%) had stage 4 disease. For ovarian serous patients, stage, grade, optimality, neoadjuvant chemotherapy, adjuvant chemotherapy cycle number, and recurrence had impact on both overall and disease-free survival (p < 0.05). For uterine serous cancer patients, optimality was the only prognostic factor for both survival and recurrence (p = 0.01 and p = 0.01, respectively). Conclusion: In ovarian serous cancer patients, we found that disease stage, grade, optimality, neoadjuvant chemotherapy, and adjuvant chemotherapy cycle number had impact on overall and disease-free survival in both univariate and multivariate Cox regression analysis, whereas disease stage and optimality were the only significant prognostic factors for recurrence in ovarian serous cancer patients. However, in patients with uterine serous carcinomas, optimal surgery was the only independent prognostic factor both for survival and recurrence.

The Assessment of IL-21 and IL-22 at the mRNA Level in Tumor Tissue and Protein Concentration in Serum and Peritoneal Fluid in Patients with Ovarian Cancer

The aim of the analysis was for the first time to assess the expression of genes encoding IL-21 and IL-22 at the mRNA level in ovarian tumor specimens and the concentration of these parameters in serum and peritoneal fluid in patients with ovarian serous cancer. The levels of IL-21 and IL-22 transcripts were evaluated with the use of the real-time RT-qPCR. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of proteins. Quantitative analysis of IL-21 gene mRNA in the tumor tissue showed the highest activity in the G1 degree of histopathological differentiation and was higher in G1 compared to the control group. The concentration of IL-21 and IL-22 in the serum and in the peritoneal fluid of women with ovarian cancer varied depending on the degree of histopathological differentiation of the cancer and showed statistical variability compared to controls. The conducted studies have shown that the local and systemic changes in the immune system involving IL-21 and IL-22 indicate the participation of these parameters in the pathogenesis of ovarian cancer, and modulation in the IL-21/IL-22 system may prove useful in the development of new diagnostic and therapeutic strategies used in patients, which require further research.

Identification of Tumor Microenvironment-Related Prognostic Biomarkers for Ovarian Serous Cancer 3-Year Mortality Using Targeted Maximum Likelihood Estimation: A TCGA Data Mining Study

Ovarian serous cancer (OSC) is one of the leading causes of death across the world. The role of the tumor microenvironment (TME) in OSC has received increasing attention. Targeted maximum likelihood estimation (TMLE) is developed under a counterfactual framework to produce effect estimation for both the population level and individual level. In this study, we aim to identify TME-related genes and using the TMLE method to estimate their effects on the 3-year mortality of OSC. In total, 285 OSC patients from the TCGA database constituted the studying population. ESTIMATE algorithm was implemented to evaluate immune and stromal components in TME. Differential analysis between high-score and low-score groups regarding ImmuneScore and StromalScore was performed to select shared differential expressed genes (DEGs). Univariate logistic regression analysis was followed to evaluate associations between DEGs and clinical pathologic factors with 3-year mortality. TMLE analysis was conducted to estimate the average effect (AE), individual effect (IE), and marginal odds ratio (MOR). The validation was performed using three datasets from Gene Expression Omnibus (GEO) database. Additionally, 355 DEGs were selected after differential analysis, and 12 genes from DEGs were significant after univariate logistic regression. Four genes remained significant after TMLE analysis. In specific, ARID3C and FREM2 were negatively correlated with OSC 3-year mortality. CROCC2 and PTF1A were positively correlated with OSC 3-year mortality. Combining of ESTIMATE algorithm and TMLE algorithm, we identified four TME-related genes in OSC. AEs were estimated to provide averaged effects based on the population level, while IEs were estimated to provide individualized effects and may be helpful for precision medicine.

The Prevalence, Associated Factors for Lung Metastases Development and Prognosis in Ovarian Serous Cancer Based on SEER Database

Ovarian carcinoma (OC) is one of the 3 most common gynecological malignancies, and the prognosis of patients with lung metastasis was the worst. SEER documented OC patients, diagnosed between 2010 and 2016, were included in the study. Univariable and multivariable logistic regression analyses were performed to identify associated factors for lung metastases (LM) development. Kaplan–Meier analysis was used to estimate the overall survival for OC patients with LM. A total of 10146 eligible serous ovarian cancer (SOC) patients were included, the prevalence of LM was 3.77% (N = 378). Patients with T4 stage (χ2 = 128.515; P = 0.000), N1 stage (χ2 = 49.536; P = 0.000), right laterality (χ2 = 18.756; P = 0.000) (compared with left side), undifferentiated grade (χ2 = 36.174; P = 0.000), bone metastasis (χ2 = 183.529); P = 0.000), brain metastasis (χ2 = 117.539; P = 0.000), liver metastasis (χ2 = 442.472; P = 0.000) had a larger probability of LM than other groups. Results showed that T3/N1 stage, bone metastases, liver metastases, chemotherapy, surgery were positively correlated with LM. Multivariable cox analysis showed that age, bone metastasis, no chemotherapy, no surgery were independent risk factors in SOC-LM patients. This study provided new research insights on the prevalent LM in patients with SOC. The factors associated with LM development and prognosis can be potentially used for LM early screening and professional care.