Development and validation of a nomogram (APGRC) to predict the presence of germline DNA damage repair pathogenic variants in Asian patients with prostate cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhang T
PROVIDER: S-EPMC10497832 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
Publications
Development and validation of a nomogram (APGRC) to predict the presence of germline DNA damage repair pathogenic variants in Asian patients with prostate cancer.
Zhang Tingwei T Wei Yu Y Hong Boon Hao BH Sumiyoshi Takayuki T Ong Enya Hui Wen EHW Zeng Hao H Li Yonghong Y Ng Chi-Fai CF Pan Jian J Fang Bangwei B Wang Beihe B Wu Junlong J Wang Hongkai H Akamatsu Shusuke S Chua Melvin Lee Kiang MLK Ye Dingwei D Zhu Yao Y
Clinical and translational medicine 20230901 9
Similar Datasets
Project description:PurposeWhite matter damage (WMD) was defined as the appearance of rough and uneven echo enhancement in the white matter around the ventricle. The aim of this study was to develop and validate a risk prediction model for neonatal WMD.Materials and methodsWe collected data for 1,733 infants hospitalized at the Department of Neonatology at The First Affiliated Hospital of Zhengzhou University from 2017 to 2020. Infants were randomly assigned to training (n = 1,216) or validation (n = 517) cohorts at a ratio of 7:3. Multivariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to establish a risk prediction model and web-based risk calculator based on the training cohort data. The predictive accuracy of the model was verified in the validation cohort.ResultsWe identified four variables as independent risk factors for brain WMD in neonates by multivariate logistic regression and LASSO analysis, including gestational age, fetal distress, prelabor rupture of membranes, and use of corticosteroids. These were used to establish a risk prediction nomogram and web-based calculator (https://caowenjun.shinyapps.io/dynnomapp/). The C-index of the training and validation sets was 0.898 (95% confidence interval: 0.8745-0.9215) and 0.887 (95% confidence interval: 0.8478-0.9262), respectively. Decision tree analysis showed that the model was highly effective in the threshold range of 1-61%. The sensitivity and specificity of the model were 82.5 and 81.7%, respectively, and the cutoff value was 0.099.ConclusionThis is the first study describing the use of a nomogram and web-based calculator to predict the risk of WMD in neonates. The web-based calculator increases the applicability of the predictive model and is a convenient tool for doctors at primary hospitals and outpatient clinics, family doctors, and even parents to identify high-risk births early on and implementing appropriate interventions while avoiding excessive treatment of low-risk patients.
| S-EPMC7940363 | biostudies-literature
Project description:PurposeGermline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood.Patients and methodsTo evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A, and HOXB13 in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses.ResultsAll pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A/HOXB13, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2. It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or HOXB13 G84E mutations.ConclusionThese findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.
| S-EPMC7446531 | biostudies-literature
Project description:More knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused and pan-ancestry case-control analyses to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1,147 individuals with pediatric sarcoma diagnoses (226 Ewing sarcoma, 438 osteosarcoma, 180 rhabdomyosarcoma, and 303 other sarcoma) relative to identically processed cancer-free control individuals. Findings in Ewing sarcoma were validated with an additional cohort of 430 individuals, and a subset of 301 Ewing sarcoma parent-proband trios was analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the European Ewing sarcoma discovery cohort (three individuals, OR 12.6, 95% CI 3.0-43.2, p = 0.003, FDR = 0.40). This enrichment in FANCC heterozygous pathogenic variants was again observed in the European Ewing sarcoma validation cohort (three individuals, OR 7.0, 95% CI 1.7-23.6, p = 0.014), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in individuals with Ewing sarcoma. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.
| S-EPMC9247831 | biostudies-literature
Project description:BackgroundGrowing evidence suggests a role for cancer susceptibility genes such as BRCA2 and PALB2 in young-onset colorectal cancers. Using a cohort of young colorectal cancer patients, we sought to identify and provide functional evidence for germline pathogenic variants of DNA repair genes not typically associated with colorectal cancer.MethodsWe recruited 88 patients with young-onset colorectal cancers seen at a general oncology center. Whole-exome sequencing was performed to identify variants in DNA repair and colorectal cancer predisposition genes. Pathogenic BRCA2 and PALB2 variants were analyzed using immunoblot and immunofluorescence on patient-derived lymphoblastoid cells.ResultsIn general, our cohort displayed characteristic features of young-onset colorectal cancers. Most patients had left-sided tumors and were diagnosed at late stages. Four patients had familial adenomatous polyposis, as well as pathogenic APC variants. We identified 12 pathogenic variants evenly distributed between DNA repair and colorectal cancer predisposition genes. Six patients had pathogenic variants in colorectal cancer genes: APC (n = 4) and MUTYH monoallelic (n = 2). Another six had pathogenic variants in DNA repair genes: ATM (n = 1), BRCA2 (n = 1), PALB2 (n = 1), NTHL1 (n = 1), and WRN (n = 2). Pathogenic variants BRCA2 c.9154C>T and PALB2 c.1059delA showed deficient homologous recombination repair, evident from the impaired RAD51 nuclear localization and foci formation.ConclusionA substantial portion of pathogenic variants in young-onset colorectal cancer was found in DNA repair genes not previously associated with colorectal cancer. This may have implications for the management of patients. Further studies are needed to ascertain the enrichment of pathogenic DNA repair gene variants in colorectal cancers.
| S-EPMC6649855 | biostudies-literature
Project description:BackgroundPSMA-negative but FDG-positive (PSMA-/FDG+) lesion in dual-tracer (68Ga-PSMA and 18F-FDG) positron emission tomography/computed tomography (PET/CT) is associated with an unfavorable response to Lutetium-177 (177Lu)-PSMA-617. This study sought to develop both radiomics and clinical models for the precise prediction of the presence of PSMA-/FDG+ lesions in patients with castration-resistant prostate cancer (CPRC).MethodsA cohort of 298 patients who underwent dual-tracer PET/CT with a less than 5-day interval was included. The evaluation of the prognostic performance of the radiomics model drew upon the survival data derived from 40 patients with CRPC treated with 177Lu-PSMA-617 in an external cohort. Two endpoints were evaluated: (a) prostate-specific antigen (PSA) response rate, defined as a reduction exceeding 50% from baseline and (b) overall survival (OS), measured from the initiation of 177Lu-PSMA-617 to death from any cause.ResultsPSMA-/FDG+ lesions were identified in 56 (18.8%) CRPC patients. Both radiomics (area under the curve [AUC], 0.83) and clinical models (AUC, 0.78) demonstrated robust performance in PSMA-/FDG+ lesion prediction. Decision curve analysis revealed that the radiomics model yielded a net benefit over the 'screen all' strategy at a threshold probability of ⩾4%. At a 5% probability threshold, the radiomics model facilitated a 21% reduction in 18F-FDG PET/CT scans while only missing 2% of PSMA-/FDG+ cases. Patients with a low estimated score exhibited significantly prolonged OS (hazard ratio = 0.49, p = 0.029) and a higher PSA response rate (75% versus 35%, p = 0.011) compared to those with a high estimated score.ConclusionThis study successfully developed two models with accurate estimations of the risk associated with PSMA-/FDG+ lesions in CRPC patients. These models held potential utility in aiding the selection of candidates for 177Lu-PSMA-617 treatment and guiding 68Ga-PSMA PET/CT-directed radiotherapy.
| S-EPMC10771757 | biostudies-literature
Project description:In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.
| S-EPMC8924169 | biostudies-literature
Project description:PurposeProstate cancer is one of the most heritable cancers and prostate cancer with germline mutations is associated with aggressive features and a poor prognosis. We investigated germline variants in unselected Korean men with prostate cancer.Materials and methodsIn this study, we prospectively collected buccal swab DNA from 120 unselected Korean men with prostate cancer, and performed massively parallel sequencing. Identified germline variants were interpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology 2015 guidelines.ResultsOf the 120 patients, 30 had regional or metastatic disease and 10, 34, 25, and 21 patients were categorized as having low, intermediate, high, or very high-risk disease, respectively. Of the 88 germline variants, 6 pathologic or likely pathogenic variants were identified in 7 patients (5.8%) with BRCA2 (1.7%), HOXB13 (1.7%), PALB2 (0.8%), ATM (0.8%), and MSH2 (0.8%). Of 7 patients, 2 possessed intermediate risk disease that was not included in the recommendation for genetic testing. We identified the Gly132Glu variant, which was different from the Gly84Glu variant of the HOXB13 gene in Western populations.ConclusionsThis study presents the first analysis of germline variants in unselected Korean men with prostate cancer. Our results showed comparable germline prevalence with previous studies and provides evidence for the necessity of genetic testing in Korean men with prostate cancer.
| S-EPMC9091831 | biostudies-literature
Project description:Pathogenic germline variants in cancer-associated genes are risk factors for cancer predisposition. However, systematic mining and summarizing of cancer pathogenic or likely pathogenic variants has not been performed for people of East Asian descent. This study aimed to investigate publicly available data to identify germline variants in East Asian cancer cohorts and compare them to variants in Caucasian cancer cohorts. Based on the data we retrieved, we built a comprehensive database, named COGVIC (Catalog of Germline Variants in Cancer). A total of 233 variants in the East Asian population were identified. The majority (87%) of genes with cancer-associated variants were not shared between the East Asian and Caucasian cohorts. This included pathogenic variants in BRCA2. Our study summarized the prevalence of germline variants in East Asian cancer cohorts and provides an easy-to-use online tool to explore germline mutations related to cancer susceptibility. http://www.cogvic.vip/.
| S-EPMC8730286 | biostudies-literature
Project description:ObjectiveWe aimed to develop and validate a nomogram based on MRI radiomics to predict overall survival (OS) for patients with de novo oligometastatic prostate cancer (PCa).MethodsA total of 165 patients with de novo oligometastatic PCa were included in the study (training cohort, n = 115; validating cohort, n = 50). Among them, MRI scans were conducted and T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) sequences were collected for radiomics features along with their clinicopathological features. Radiological features were extracted from T2WI and ADC sequences for prostate tumors. Univariate Cox regression analysis and the least absolute shrinkage and selection operator (LASSO) combined with 10-fold cross-validation were used to select the optimal features on each sequence. Then, a weighted radiomics score (Rad-score) was generated and independent risk factors were obtained from univariate and multivariate Cox regressions to build the nomogram. Model performance was assessed using receiver operating characteristic (ROC) curves, calibration, and decision curve analysis (DCA).ResultsEastern Cooperative Oncology Group (ECOG) score, absolute neutrophil count (ANC) and Rad-score were included in the nomogram as independent risk factors for OS in de novo oligometastatic PCa patients. We found that the areas under the curves (AUCs) in the training cohort were 0.734, 0.851, and 0.773 for predicting OS at 1, 2, and 3 years, respectively. In the validating cohort, the AUCs were 0.703, 0.799, and 0.833 for predicting OS at 1, 2, and 3 years, respectively. Furthermore, the clinical relevance of the predictive nomogram was confirmed through the analysis of DCA and calibration curve analysis.ConclusionThe MRI-based nomogram incorporating Rad-score and clinical data was developed to guide the OS assessment of oligometastatic PCa. This helps in understanding the prognosis and improves the shared decision-making process.
| S-EPMC11660381 | biostudies-literature
Project description:BackgroundMetastatic prostate cancer (mPCa) complicates treatment due to its unpredictable progression. Current prognostic tools often lack precision. This study aimed to develop an effective tool to predict overall survival (OS) in mPCa patients undergoing radiotherapy, thereby addressing the clinical need for personalized treatment decisions.MethodsA total of 1,171 mPCa patients receiving radiotherapy between 2004 and 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Patients with distant metastases and complete data on prostate-specific antigen (PSA), Gleason score (GS), and tumor-node-metastasis (TNM) staging were included. The cohort was randomly divided into a training set (n=819) and an internal validation set (n=352). Independent prognostic factors, including age, marital status, PSA, GS, T-stage, M-stage, and chemotherapy, were used to construct a nomogram. The external validation cohort comprised 138 mPCa patients from The First Affiliated Hospital of Nanchang University, with survival outcomes followed through their medical records.ResultsIn the SEER cohort, 67.7% of patients were married, 74.3% were White, and 23.2% had a GS of 7. The external validation cohort had a mean survival of 45.8 months. The nomogram's area under the curve (AUC) values for predicting 1-, 3-, and 5-year OS were 0.686, 0.679, and 0.724 in the training cohort; 0.713, 0.732, and 0.711 in the internal validation cohort; and 0.748, 0.735, and 0.750 in the external validation cohort, respectively. Calibration plots demonstrated reasonable agreement between predicted and observed survival rates, but the AUC values indicate moderate predictive performance.ConclusionsAlthough the nomogram offers some clinical value in estimating survival for mPCa patients receiving radiotherapy, its predictive accuracy remains moderate. Further refinements incorporating additional prognostic factors may enhance its clinical utility.
| S-EPMC11635567 | biostudies-literature