Ovarian Cancer Susceptibility Research Articles

Mutation characteristics of cancer susceptibility genes in Chinese ovarian cancer patients.

The association between mutations in susceptibility genes and the occurrence of ovarian cancer has been extensively studied. Previous research has primarily concentrated on genes involved in the homologous recombination repair pathway, particularly BRCA1 and BRCA2. However, a wider range of genes related to the DNA damage response pathways has not been fully explored. To investigate the mutation characteristics of cancer susceptibility genes in the Chinese ovarian cancer population and the associations between gene mutations and clinical data, this study initially gathered a total of 1171 Chinese ovarian cancer samples and compiled a dataset of germline mutations in 171 genes. In this study, it was determined that MC1R and PRKDC were high-frequency ovarian cancer susceptibility genes in the Chinese population, exhibiting notable distinctions from those in European and American populations; moreover high-frequency mutation genes, such as MC1R: c.359T>C and PRKDC: c.10681T>A, typically had high-frequency mutation sites. Furthermore, we identified c.8187G>T as a characteristic mutation of BRCA2 in the Chinese population, and the CHEK2 mutation was significantly associated with the early onset of ovarian cancer, while the CDH1 and FAM175A mutations were more prevalent in Northeast China. Additionally, Fanconi anemia pathway-related genes were significantly associated with ovarian carcinogenesis. In summary, this research provided fundamental data support for the optimization of ovarian cancer gene screening policies and the determination of treatment, and contributed to the precise intervention and management of patients.

Associations of PD-1 and PD-L1 gene polymorphisms with cancer risk: a meta-analysis based on 50 studies.

Programmed death-1 and its ligand-1 (PD-1/PD-L1), immune checkpoints proteins, play a crucial role in anti-tumor responses. A large number of studies have evaluated the relationships of PD-1/PD-L1 polymorphisms with risk of cancer, but evidence for the associations remains inconsistent. Therefore, we performed a meta-analysis to examine the associations between PD-1/PD-L1 single nucleotide polymorphisms (SNPs) and cancer predisposition. Results showed that PD-1.3 and PD-L1 rs17718883 were significantly correlated with overall cancer risk. PD-1.5 was prominently linked with cervical cancer (CC), non-small cell lung cancer (NSCLC), TC (thyroid cancer), brain tumor, AML (acute myelocytic leukemia) and UCC (urothelial cell carcinoma) risk, PD-1.9 with breast cancer (BC), AML, esophageal cancer (EC) and ovarian cancer (OC) risk, and PD-1.3 with colorectal cancer (CRC) and BCC (basal cell carcinoma) risk. PD-1.1 polymorphism slightly elevated BC and OC susceptibility, whereas the rs4143815 variant notably decreased the risk of gastric cancer (GC), hepatocellular carcinoma (HCC) and OC, but increased the risk of BC. PD-1.6 was closely linked with AML risk, PD-L1 rs2890658 with NSCLC, HCC and BC risk, rs17718883 with HCC and GC risk, rs10815225 with GC risk, and rs2297136 with NSCLC and HCC risk. Interestingly, the rs7421861, rs10815225, and rs10815225 markedly reduced cancer susceptibility among Asians. The rs7421861 polymrophism decreased cancer risk among Caucasians, rather than the rs10815225 elevated cancer risk. Our results supported that PD-1 and PD-L1 SNPs were dramatically correlated with cancer risk.

Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China

DNA damage response (DDR) pathways are responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cellular genome, including homologous recombination repair (HRR) pathway, mismatch repair (MMR) pathway, etc. In ovarian cancer, current studies are focused on HRR genes, especially BRCA1/2, and the results show regional and population differences. To characterize germline mutations in DDR genes in ovarian cancer in Southwest China, 432 unselected ovarian cancer patients underwent multi-gene panel testing from October 2016 to October 2020. Overall, deleterious germline mutations in DDR genes were detected in 346 patients (80.1%), and in BRCA1/2 were detected in 126 patients (29.2%). The prevalence of deleterious germline mutations in BRCA2 is higher than in other studies (patients are mainly from Eastern China), and so is the mismatch repair genes. We identified three novel BRCA1/2 mutations, two of which probably deleterious (BRCA1 p.K1622* and BRCA2 p.L2987P). Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. In conclusion, our study highlights the necessity of comprehensive germline mutation detection of DNA damage response genes in ovarian cancer patients, which is conducive to patient management and genetic counseling.

BRCA1 and Its Vulnerable C-Terminal BRCT Domain: Structure, Function, Genetic Mutations and Links to Diagnosis and Treatment of Breast and Ovarian Cancer.

The BRCA1 is a tumor suppressor gene that encodes for the BRCA1 protein, which plays a vital role in DNA repair, cell cycle regulation, and the maintenance of genomic stability. The BRCA1 protein interacts with a variety of other proteins that play essential roles in gene regulation and embryonic development. It is a large protein composed of multiple domains. The C-terminal region of the BRCA1 protein consists of two BRCT domains connected by a short linker. The BRCT domains are crucial in protein-protein interactions as well as in DNA damage response and cell cycle regulation through their phosphoprotein binding modules that recognize the phosphorylated protein sequence motif of other kinases. Mutations within the BRCT domain can disrupt the normal function of BRCA1 and lead to an increased risk of developing breast and ovarian cancer. Herein, we explore the structural characteristics of BRCA1, focusing on the BRCT domain, its interactions with key cellular components, and its involvement in various cellular processes. In addition, the impact of BRCT domain mutations on breast and ovarian cancer susceptibility, prognosis, and treatment options is discussed. By providing a comprehensive understanding of the BRCT domain of BRCA1, this review aims to shed light on the role of this important domain in the pathogenesis and potential therapeutic approaches for breast and ovarian cancer.

Biomarkers for Early Detection of Ovarian Cancer: A Review

Ovarian cancer, with its asymptomatic early stages, poses a significant challenge for early diagnosis and survival improvement. The utilization of tumor markers, including CA -125 and HE4 has become crucial in detecting these silent killers. Additionally, gene-based markers like BRCA1 and BRCA2 mutations are increasingly acknowledged for indicating ovarian cancer susceptibility. Promising emerging biomarkers, such as microRNAs and circulating tumor cells, offer new research avenues and diagnostic possibilities for the early detection of ovarian cancer. This article provides a comprehensive review of current specific markers, gene-based indicators, emerging markers, and other notable approaches in the early identification of ovarian cancer.

A Novel Germline Mutation of BRCA1 and Integrated Analysis With Somatic Mutation in a Chinese Multi-Cancer Family.

The presence of mutations in the BRCA1 gene (MIM: 113705) is widely recognized as a significant genetic predisposition for ovarian cancer. This study investigated the genomic mutations in a Chinese family with a history of ovarian, breast, and rectal adenocarcinoma. A novel germline mutation (Phe1695Val) in BRCA1 was identified through whole-exome sequencing. Subsequently, we performed whole-genome sequencing to identify somatic mutations and analyze mutational signatures in individuals carrying the novel germline mutation. Our findings revealed a correlation between somatic mutational signatures and the BRCA1 germline mutation in the proband with ovarian cancer, while no such association was observed in the tumor tissue from the patient with breast cancer. Furthermore, distinct somatic driver mutations were identified, a truncated mutation in the TP53 gene in the ovarian tumor tissue, and a hotspot mutation in the PIK3CA gene in the breast cancer. According to our findings, the BRCA1 F1695V mutation is linked to ovarian cancer susceptibility in the family and causes specific somatic mutational profiles.

Relationship between PIWIL1 gene polymorphisms and epithelial ovarian cancer susceptibility among southern Chinese woman: a three-center case–control study

ObjectiveTo investigate the potential correlation between piwi-like RNA-mediated gene silencing 1 (PIWIL1) polymorphisms and susceptibility to epithelial ovarian cancer (EOC).MethodsA case–control study was conducted to evaluate the susceptibility of EOC using multinomial logistic regression analysis. The study analyzed the relationship between five functional single nucleotide polymorphisms (SNPs) in the PIWIL1 gene and EOC risk. Genotyping of 288 cases and 361 healthy samples from South China was identified using a TaqMan assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relationship between the five selected SNPs and EOC susceptibility.ResultsAmong the five SNPs analyzed, the rs10848087 G > A and rs7957349 G > C variants significantly increased the susceptibility of EOC, rs10773771 C > T was associated with a decreased risk of EOC, while the rs35997018 and rs1106042 variants were not in Hardy–Weinberg equilibrium (p < 0.05). The rs10848087 G > A was significantly associated with increased risk of EOC in individuals with metastasis, FIGO stage I and III, low and high pathological grade, tumor numbers ≤ 3 and > 3, tumor size > 3 cm and ≤ 3 cm, pregnant more than 3 times, pre-menopausal status, and strong positive expression of ER (estrogen receptor), PR (progesterone receptor), PAX8 (paired-box 8), wild-type p53 (tumor protein 53), WT1 (Wilm’s tumor gene), P16 (cyclin-dependent kinase inhibitor 2A). In addition, rs10848087 G > A enhanced the EOC risk of cases with negative/mild positive expression of wild p53 and Ki67, and with or without mutant p53 expression. The rs7957349 G > C variant was linked to an increased risk of EOC in subgroups with certain characteristics, including age equal or less than 53 years, metastasis, clinical stage I, low pathological grade, tumor number, tumor size, pregnant times, post-menopause, pre-menopause, and strong positive expression of wild p53 and Ki67 (Antigen identified by monoclonal antibody Ki-67), as well as without mutant p53 expression. The rs10773771 CT/TT alleles were identified to have a protective effect on EOC in women aged 53 years or older, as well as in cases with metastasis, advanced clinical stage, high pathological grade, multiple tumors, tumor size equal to or less than 3 cm, history of pregnancy, post-menopausal status, and strong positive expression of ER, PR, wild-type p53, PAX8, WT1, P16, and Ki67. Furthermore, rs10773771 CT/TT also showed a protective effect in patients with negative or mildly positive expression of PR, PAX8, wild-type p53, WT1, and P16, as well as positive expression of mutant p53. Compared to the reference haplotype GCG, individuals harboring haplotypes GTG were found to have a significantly decreased susceptibility to EOC. PIWIL1 was significantly expressed in the thyroid, pituitary, and adrenal glands with rs7957349 CC alleles.ConclusionsPIWIL1 rs10848087 and rs7957349 were associated with increased risk of EOC, while rs10773771 may have a protective effect against EOC. These genetic variants may serve as potential biomarkers for EOC susceptibility in the South China population.

RIPK1 polymorphisms and expression levels: impact on genetic susceptibility and clinical outcome of epithelial ovarian cancer

BackgroundThe aim of this study was to explore the associations of RIPK1 polymorphisms, plasma levels and mRNA expression with susceptibility to epithelial ovarian cancer (EOC) and clinical outcome.MethodsThree hundred and nineteen EOC patients included in a 60-month follow-up program and 376 controls were enrolled. Two tag SNPs (rs6907943 and rs9392453) of RIPK1 were genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) method. Plasma levels of RIPK1 and RIPK1 mRNA expression in white blood cells were determined by ELISA and qPCR, respectively.ResultsFor rs9392453, significantly increased EOC risk was found to be associated with C allele (P = 0.002, OR = 1.49, 95%CI 1.15–1.92), and with CT/CC genotypes in the dominant genetic model (P = 0.006, OR = 1.54, 95%CI 1.12–2.08). CC haplotype (rs6907943-rs9392453) was associated with increased EOC susceptibility. CC genotype of rs6907943 and CT/CC genotypes of rs9392453 were associated with early onset (age ≤ 50 years) of EOC (OR = 2.5, 95%CI 1.03–5.88, and OR = 1.64, 95%CI 1.04–2.63, respectively). AC genotype of rs6907943 was associated with better overall survival of EOC patients in the over-dominant genetic model (P = 0.035, HR = 0.41, 95%CI 0.18–0.94). Multivariate survival analysis identified the AC genotype of rs6907943 as an independent protective factor for survival of early onset patients (P = 0.044, HR = 0.12, 95%CI 0.02–0.95). Compared to controls, significantly increased plasma levels of RIPK1 and reduced RIPK1 mRNA expression were observed in patients.ConclusionsOur results suggest that tag SNPs of RIPK1, increased plasma levels of RIPK1 protein and reduced RIPK1 mRNA expression in white blood cells, may influence the susceptibility to EOC. SNP rs6907943 may be a useful marker to distinguish EOC patients with high risk of death.

Mutation analysis of the TERT gene in ovarian cancer patients of the Turkish population by next generation sequencing method.

Ovarian cancer (OC) ranks seventh among malignant tumors worldwide. As one of the most common gynecological malignancies, ovarian cancer has the second-highest mortality rate, after cervical and uterine cancer. Next-Generation Sequencing (NGS) technology has enhanced multi-gene panel analysis and its clinical utility for identifying cancer-causing gene mutations. This study aimed to determine the presence of significant and nonsense mutations in telomerase reverse transcriptase (TERT), alpha-thalassemia/mental retardation, X-linked (ATRX), O-6-methylguanine-DNA methyltransferase (MGMT), and isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes using the Next-Generation Sequencing (NGS) method. A cohort of 33 patients diagnosed with ovarian cancer was included in this investigation, and peripheral blood samples were collected from all participants. Significant and nonsense mutations in TERT, ATRX, MGMT, IDH1, and IDH2 genes were detected using the Next-Generation Sequencing method. Bioinformatics analysis was conducted using the QIAGEN Clinical Insight system. Twenty-four patients exhibited seven different TERT mutations, occurring in both exonic and intronic regions. One patient displayed a c.699-3delC deletion in the intronic region of the IDH1 gene, and the c.532G > A (p.V178I) mutation observed in three patients was assessed as potentially harmful. Additionally, novel mutations c.881A > G and c.995A > G were observed in the ATRX gene. The heterozygous novel mutation identified in the ATRX gene was confirmed through Sanger sequencing. These mutations were not previously associated with ovarian cancer and are considered novel candidate markers for ovarian cancer susceptibility. Confirmation of these results through larger cohort studies or functional investigations will contribute to a better understanding of the molecular mechanisms underlying ovarian cancer.

Search for Novel Hereditary Ovarian Cancer Susceptibility Genes through Whole Exome Sequencing of Responders to Platinum-Based Therapy

Введение. Данные клинических наблюдений свидетельствуют, что опухоли яичника и некоторые другие разновидности карцином демонстрируют выраженный ответ на производные платины или схожие препараты, если у пациентки есть наследственные мутации BRCA1/2 или других генов ДНК-репарации. Изучение BRCA1/2-негативных раков яичника (РЯ), которые продемонстрировали хороший ответ на платиносодержащую терапию, представляется перспективным подходом к поиску новых генов наследственного рака. Цель. Поиск новых генетических детерминант РЯ в коллекции случаев, сформированной на основе сведений о клинической эффективности первичного лечения. Материалы и методы. Образцы ДНК 123 пациенток с продолжительной клинической ремиссией были подвергнуты трехэтапному анализу: 1) тестирование распространенных мутаций BRCA1/2; 2) таргетное секвенирование генов, ассоциированных с наследственными раками (ATM, BLM, BRCA1, BRCA2, CDH1, CHEK2, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, NF2, PALB2, PMS2, POLD1, POLE, PTCH1, PTEN, RAD51C, RAD51D, RB1, TP53, TSC1, TSC2, WRN) 3) полноэкзомное секвенирование. Результаты. В группе 123 РЯ был обнаружен 41 (33 %) случай носительства мутаций BRCA1/2 и семь случаев носительства патогенных вариантов ATM, BLM, NBN (n = 3), PALB2 и RAD51D. По результатам полноэкзомного анализа отобрано 12 генов, в которых были обнаружены инактивирующие варианты и продукты которых вовлечены в различные аспекты канцерогенеза: AEN, ATF5, BRIP1, CEBPA, FANCM, GREB1, GRWD1, P4HTM, POLA2, RAD50, RAD54B, STK36. У пациенток, носительниц инактивирующих вариантов в генах ATF5 и P4HTM, в опухоли наблюдалась потеря гетерозиготности в локусе соответствующего гена. Исследование дополнительной когорты последовательных диагностических РЯ (n = 107) позволило идентифицировать еще три инактивирующих варианта в отобранных генах-кандидатах — ATF5, BRIP1 и FANCM. Заключение. Пациенты c хорошим ответом на платиносодержащую терапию представляют собой перспективную категорию для поиска новых генов, ассоциированных с наследственным РЯ.

Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer

BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

GCPBayes pipeline: a tool for exploring pleiotropy at thegene level.

Cross-phenotype association using gene-set analysis can help to detect pleiotropic genes and inform about common mechanisms between diseases. Although there are an increasing number of statistical methods for exploring pleiotropy, there is a lack of proper pipelines to apply gene-set analysis in this context and using genome-scale data in a reasonable running time. We designed a user-friendly pipeline to perform cross-phenotype gene-set analysis between two traits using GCPBayes, a method developed by our team. All analyses could be performed automatically by calling for different scripts in a simple way (using a Shiny app, Bash or R script). A Shiny application was also developed to create different plots to visualize outputs from GCPBayes. Finally, a comprehensive and step-by-step tutorial on how to use the pipeline is provided in our group's GitHub page. We illustrated the application on publicly available GWAS (genome-wide association studies) summary statistics datato identify breast cancer and ovarian cancer susceptibility genes. We have shown that the GCPBayes pipeline could extract pleiotropic genes previously mentioned in the literature, while it also provided new pleiotropic genes and regions that are worthwhile for further investigation. We have also provided some recommendations about parameter selection for decreasing computational time of GCPBayes on genome-scale data.

Screening mitophagy-related lncRNAs based on WGCNA to identify and validate a prognostic signature for patients with ovarian cancer.

e17554 Background: Mitophagy refers to the process by which cells selectively remove incomplete or damaged mitochondria through the autophagic mechanism. However, the value of mitophagy-related genes (MRGs) and mitophagy-related lncRNAs (MRLs) in ovarian cancer (OC) is still not clear. Methods: We explored the alterations of MRGs in four gynecological tumors using R packages. Based on weighted coexpression network analysis (WGCNA), MRLs were identified to carry out LASSO Cox regression analysis and then we established the prognostic MRL-signature. The prognosis and independent prognostic value of the MRL-signature was also validated by four independent datasets from GEO. The expression level of MRLs involved in the prognostic signature we established were detected by qPCR for the samples we collected. Analysis for characteristics of functional pathways, immunity status, and anti-tumor therapy were based on GSEA, ssGSEA, CIBERSORT, xCELL, MCPcounter, ESTIMATE, and TIDE. The ceRNA network was constructed applying miranda, miRWalk3.0, and Cytoscape. Results: Most MRGs were found at lower expression levels in four gynecological tumors. Among the four gynecological tumors, the levels of CNV and MRGs were positively correlated. Most MRGs were negatively correlated with methylation level. A total of 52 MRGs were differentially expressed in OC tissues. Nine MRLs were significantly associated with survival prognosis. Eight optimal lncRNA combinations were screened by LASSO Cox Regression algorithm. On the basis of Univariate Cox regression and Multivariate Cox regression analyses, the risk model based on MRLs was proved to be the independent prognostic factors. The qPCR assay showed that the differential expression trends of these MRLs in our collected OC samples were consistent with those in TCGA database. We found that TIDE score of OC patients with lower risk score was lower, suggesting that OC patients with low RSs are more sensitive to immune checkpoint blockade therapy. OC patients with higher risk score had higher immune cell scores and higher risk score correlated strongly with higher stromal and estimated scores, while lower risk score correlated with tumor purity. We found that the IC50 levels of paclitaxel and ABT.888 (Veliparib) in the high-risk group were observably higher than those in the low-risk group, suggesting a negative correlation between risk score and the drug susceptibility of OC. There were 539 miRNAs, 73 mRNAs and 8 lncRNAs in the ceRNA network. Conclusions: The integrative analysis of MRGs and MRLs revealed their roles in prognosis and therapeutic responsibility in chemotherapy and immunotherapy. Our findings demonstrate the important clinical significance of the signature based on MRLs, and will help improve clinical outcomes for patients with OC.

Genetic counseling and testing for epithelial ovarian cancer in a diverse patient population.

e17563 Background: According to the current American Society of Clinical Oncology (ASCO) guidelines, “all women diagnosed with epithelial ovarian cancer should be offered germline genetic testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes, irrespective of their clinical features or family history”. Test results have implications for surveillance, familial testing, and treatment. We investigated how genetic counseling and testing rates at a New York City tertiary care center with a large minority population compared with national rates, and if any disparities existed. Methods: This is a retrospective cohort study of patients with newly diagnosed epithelial ovarian, fallopian tube, peritoneal cancer between January 2014 and June 2022. Data were obtained from pathology and chemotherapy databases at the NewYork-Presbyterian Brooklyn Methodist Hospital. Variables including age, race, ethnicity, BMI, insurance, language, family history of cancer, date of diagnosis, stage, and genetic counseling/testing status were manually extracted. Descriptive statistics were used to characterize the variables of interest. Chi-square/Fisher’s exact tests were used to examine the association between genetic counseling/testing and categorical variables. Wilcoxon rank-sum/t-tests were used for association between continuous factors. The Mann-Kendall trend test was used to assess year-to-year trends. Results: 144 patients were identified. Mean age at diagnosis was 63 years (SD:13). This diverse cohort included 51% white, 36% black, 3.5% Asian, 9% other/unknown; 9% were of Hispanic ethnicity and 26% were non-English speaking. 104 (72%) patients received genetic counseling and 99 (69%) received subsequent genetic testing. 95% of those that underwent genetic counseling underwent subsequent testing. The genetic counseling and testing rates were not influenced by race, ethnicity, language, insurance type, BMI, family history of cancer. It was associated with significant difference by cancer stage (p &lt; 0.01). There was a significant upward trend of proportion of patients that received genetic counseling from 47% in 2015 to 100% in 2022 (p &lt; 0.01). Most genetic counseling was performed by a gynecologic oncologist (93%) as opposed to a genetic counselor (6.7%). Overall, 12 (8.3%) patients were BRCA+. Conclusions: Genetic counseling and testing rates within this diverse study population proved to be at least twice as high as the national average of 10-30%, with an increasing year-to-year trend. There were no disparities observed, in contrast to previously published data. BRCA mutation detection was in line with established prevalence within ovarian cancer, indicating adequate screening. Concentrated efforts on behalf of oncologists ensures excellent access to testing.

Validation of the BOADICEA model for predicting the likelihood of carrying pathogenic variants in eight breast and ovarian cancer susceptibility genes

BOADICEA is a comprehensive risk prediction model for breast and/or ovarian cancer (BC/OC) and for carrying pathogenic variants (PVs) in cancer susceptibility genes. In addition to BRCA1 and BRCA2, BOADICEA version 6 includes PALB2, CHEK2, ATM, BARD1, RAD51C and RAD51D. To validate its predictions for these genes, we conducted a retrospective study including 2033 individuals counselled at clinical genetics departments in Denmark. All counselees underwent comprehensive genetic testing by next generation sequencing on suspicion of hereditary susceptibility to BC/OC. Likelihoods of PVs were predicted from information about diagnosis, family history and tumour pathology. Calibration was examined using the observed-to-expected ratio (O/E) and discrimination using the area under the receiver operating characteristics curve (AUC). The O/E was 1.11 (95% CI 0.97–1.26) for all genes combined. At sub-categories of predicted likelihood, the model performed well with limited misestimation at the extremes of predicted likelihood. Discrimination was acceptable with an AUC of 0.70 (95% CI 0.66–0.74), although discrimination was better for BRCA1 and BRCA2 than for the other genes in the model. This suggests that BOADICEA remains a valid decision-making aid for determining which individuals to offer comprehensive genetic testing for hereditary susceptibility to BC/OC despite suboptimal calibration for individual genes in this population.

Patterns of care and outcomes of risk reducing surgery in women with pathogenic variants in non-BRCA and Lynch syndrome ovarian cancer susceptibility genes

ObjectivesGuidelines recommend risk-reducing bilateral salpingo-oophorectomy (RRSO) for women with pathogenic variants of non-BRCA and Lynch syndrome-associated ovarian cancer susceptibility genes. Optimal timing and findings at the time of RRSO for these women remains unclear. We sought to characterize practice patterns and frequency of occult gynecologic cancers for these women at our two institutions. MethodsWomen with germline ovarian cancer susceptibility gene pathogenic variants who underwent RRSO between 1/2000–9/2019 were reviewed in an IRB-approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Results26 Non-BRCA (9 BRIP1, 9 RAD51C, and 8 RAD51D) and 75 Lynch (36 MLH1, 18 MSH2, 21 MSH6) pathogenic variants carriers were identified. Median age at time of RRSO was 47. There were no occurrences of occult ovarian or fallopian tube cancer in either group. Two patients (3%) in the Lynch group had occult endometrial cancer. Median follow up was 18 and 35 months for non-BRCA and Lynch patients, respectively. No patient developed primary peritoneal cancer upon follow up. Post-surgical complications occurred in 9/101 (9%) of patients. Hormone replacement therapy (HRT) was rarely used despite reported post-menopausal symptoms in 6/25 (23%) and 7/75 (37%) patients, respectively. ConclusionsNo occult ovarian or tubal cancers were observed in either group. No recurrent or primary gynecologic-related cancers occurred upon follow-up. Despite frequent menopausal symptoms, HRT use was rare. Both groups experienced surgical complications when hysterectomy and/or concurrent colon surgery was performed suggesting concurrent surgeries should only be performed when indicated.

The association between TIPARP gene polymorphisms rs2665390 and ovarian cancer susceptibility

BackgroundOvarian cancer is taken as the most typical malignancy among women and the ninth most typical cancer in Iran. Predictive tools are of great importance as ovarian cancer is usually detected in patients at later stages of the disease. In other countries, the TIPARP gene rs2665390 has been reported to be pertinent to ovarian cancer as a risk factor. This study aims to examine if this polymorphism pertains to the risk of ovarian cancer to diagnose suitable biomarkers in the Iranian population. Method: In the present case-control piliot study, peripheral blood samples were gathered from 60 control subjects and 60 patients with ovarian cancer. The gene was determined by Tetra ARMS PCR after DNA extraction. Tetra ARMS PCR is a flexible, rapid, and cost-effective method to detect allele-specific DNA polymorphisms. The data were analyzed by chi-square test. Results: The results indicated that there was a significant association between the T/T and C/C genotypes distribution and C and T allele in ovarian cancer for rs2665390 polymorphism in the two populations. In addition, significant correlations were observed in patients with the (T/T) genotype (p = 0.0048) as frequencies of ovarian cancer decreased. Discussion & Conclusions: Based on the results, rs2665390 polymorphism of TiPARP gene might be pertained to the susceptibility of ovarian cancer in the Iranian pilot population, which can be used as a suitable biomarker for the population and help physicians with their predictions. However, more studies need to be conducted in this area to broaden our horizons on this issue.

Abstract 875: Breast cancer bioinformatics: Untangling the roles of nucleolin and BRCA1 in dysregulated DNA repair

Abstract Proteins that enable cells to sense and repair DNA damage are essential for maintaining the stability of genomes across cell divisions; dysregulation of these processes is an established hallmark of tumorigenesis. Nucleolin (NCL), a major RNA binding protein (RBP) and a caretaker tumor suppressor protein BRCA1 (the breast &amp; ovarian cancer susceptibility gene) colocalize in breast cancer. Both NCL and BRCA1 have defined roles in homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair pathways which are often dysregulated in breast cancer. BRCA1, along with a complex molecular network of signaling proteins gets recruited to damaged replication forks to initiate the HR pathway where NCL function is also implicated. However, how NCL collaborates with BRCA1 to orchestrate the complex mechanism of DNA repair under stress conditions remains unknown. To address this gap in knowledge, we have applied in silico approaches to uncover the key players which drive the molecular interactions of NCL and BRCA1 at the damaged sites. We utilized the NIH PPI, IntAct, STRING, BioGRID, GeneMania, PrePPI, and Mentha databases to derive an overlapping interactome. In this study we present a comprehensive interactome analysis and 47 proteins identified that interact with both NCL and BRCA1. As expected, majority of these common interactors participate in DNA damage damage response along with several that are implicated in regulating the gene expression via chromatin remodeling/RNA binding or controlling cell proliferation. We classified this interactome into 5 major categories based on their GO functional annotations: chromatin remodeling, DNA damage, DNA repair, RNA-binding proteins, and cell cycle. Previously, we have successfully used computational approaches to model the RNA-binding domains (RBD) of NCL and delineate the binding interfaces between NCL-RBD and a subset of miRNA that are specifically dysregulated in breast cancer. Using the same strategy, we have modeled the full length NCL to provide a complete structural representation of the protein. Our model fills the gap in missing NCL structural data, especially the unexplored N- and C - termini that may play important roles in NCL protein-protein interactions. Our results provide predicted interaction scenarios between NCL and the subset of the overlapping interactome of NCL and BRCA1, focused on DNA repair mechanisms. These in silico models are critical to understand the protein complexity at the interface of damaged DNA to identify candidates that can be targeted in breast carcinoma. Citation Format: Nitu Farhin, Andy Lam, Anjana D. Saxena, Shaneen Singh. Breast cancer bioinformatics: Untangling the roles of nucleolin and BRCA1 in dysregulated DNA repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 875.

Evaluation of genetic alterations in hereditary cancer susceptibility genes in the Ashkenazi Jewish women community of Mexico.

Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1-826-1)_(4,589+1-4,590-1)del] was also evaluated. Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs.

Screening of Exons 4-9 Polymorphisms of FTO Gene in Endometrial and Ovarian Cancers.

Endometrial and ovarian tumours are almost mechanistically affected by reproductive hormones. Ovarian cancer may be explained as metastatic or synchronous primary ovarian cancer, and the specific diagnosis is a challenge. This study aimed to investigate the mutations in fat mass and obesity-associated (FTO) genes and investigated the association of these mutations with the risk of endometrial and ovarian cancers as well as with cancer grade and stage. Blood samples were collected from 48 endometrial and ovarian cancer cases and 48 healthy women. Genomic DNA was extracted, and PCR was done to amplify FTO exons 4-9. Sanger sequencing identified 6 different novel mutations submitted to DDBJ: p.W278G and p.G284G in exon 4, p.S318I and p.A324G in exon 5 and two mutations in intron 4. Other mutations were also detected in FTO gene sequencing results, rs112997407 in intron 3, rs62033438, rs62033439, rs8048254 and rs8046502 in intron 4. The novel p.W278G, p.S318I and p.A324G mutations were predicted to be damaging. We did not find a significant association for all variables with cancer risk or clinical stage and grade except for rs62033438 variants, which showed a significant association with cancer grade, especially AA genotype (OR= 15, 95% CI:1.32 -169.88, P= 0.03). In conclusion, the statistical analysis did not clarify whether FTO mutations are implicated in cancer. Further studies with more samples are recommended to provide a more accurate picture of the correlation between FTO mutations and endometrial and ovarian cancer susceptibility.