scholarly journals Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1495
Author(s):  
Tú Nguyen-Dumont ◽  
James G. Dowty ◽  
Robert J. MacInnis ◽  
Jason A. Steen ◽  
Moeen Riaz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Prediction ◽  
Prediction Models ◽  
Risk Prediction Models ◽  
Aggressive Prostate Cancer ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Rare Genetic Variants

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.

scholarly journals Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry

2020 ◽  
pp. 32-43 ◽  
Author(s):  
Marco Matejcic ◽  
Yesha Patel ◽  
Jenna Lilyquist ◽  
Chunling Hu ◽  
Kun Y. Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Cancer Risk ◽  
African Ancestry ◽  
Prostate Cancer Risk ◽  
Aggressive Prostate Cancer ◽  
Aggressive Disease ◽  
Pathogenic Variants ◽  
Predisposition Genes

PURPOSE In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established. METHODS We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan cases and controls with prostate cancer. Rare variants were classified as pathogenic or putatively functionally disruptive and examined in association with prostate cancer risk and disease aggressiveness in gene and pathway-level association analyses. RESULTS Pathogenic variants were found in 75 of 2,098 cases (3.6%) and 31 of 1,481 controls (2.1%; odds ratio [OR], 1.82; 95% CI, 1.19 to 2.79; P = .0044), with the association being stronger for more aggressive disease phenotypes (OR, 3.10; 95% CI, 1.54 to 6.23; P = .0022). The highest risks for aggressive disease were observed with pathogenic variants in the ATM, BRCA2, PALB2, and NBN genes, with ORs ranging from approximately 4 to 15 in the combined study sample of African American and Ugandan men. Rare, nonpathogenic, nonsynonymous variants did not have a major impact on risk of overall prostate cancer or disease aggressiveness. CONCLUSION Rare pathogenic variants in DNA repair genes have appreciable effects on risk of aggressive prostate cancer in men of African ancestry. These findings have potential implications for panel testing and risk stratification in this high-risk population.

scholarly journals Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4430
Author(s):  
Greet Wieme ◽  
Jan Kral ◽  
Toon Rosseel ◽  
Petra Zemankova ◽  
Bram Parton ◽  
...  
Keyword(s):  
Ductal Adenocarcinoma ◽  
Multiple Primary Cancers ◽  
Cancer History ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Predisposition Genes ◽  
Family Cancer History ◽  
Multigene Panel Testing ◽  
Multigene Panel

(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34–0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

Recalibration of genomic risk prediction models in prostate cancer to improve individual-level predictions.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e16122-e16122
Author(s):  
Elai Davicioni ◽  
Voleak Choeurng ◽  
Bin Luo ◽  
Kasra Yousefi ◽  
Heesun Shin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Prediction ◽  
Prediction Models ◽  
Risk Prediction Models ◽  
Individual Level ◽  
Genomic Risk

Delirium incidence, risk factors, and treatment in older adults receiving chemotherapy: A scoping review.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e23025-e23025
Author(s):  
Shabbir M.H. Alibhai ◽  
Patrick Jung ◽  
Zuhair Alam ◽  
Lily Yeung ◽  
Uzair Malik ◽  
...  
Keyword(s):  
Risk Factors ◽  
Older Adults ◽  
Clinical Trials ◽  
Risk Prediction ◽  
Scoping Review ◽  
Full Text ◽  
Prediction Models ◽  
High Quality ◽  
Risk Prediction Models ◽  
Increased Risk

e23025 Background: Older adults with cancer are at increased risk of delirium given their advanced age, multiple comorbidities and medications, prevalence of cognitive impairment, and possibly cancer treatment. Awareness of such risks and interventions to prevent or treat delirium is important to clinicians and to provide high quality care. However, there is scant published information on the risks of delirium with chemotherapy or evidence-based approaches to prevent or treat it. We performed a scoping review to summarize the available evidence. Methods: We conducted a scoping review using the framework of Arksey and O’Malley. We systematically searched peer-reviewed journal articles in English, French, and German from Medline, Embase, PsychINFO, CINAHL Plus, and Cochrane Central from inception until January 2017 to identify studies that examined delirium in patients receiving chemotherapy. We also attempted to identify any studies that reported on multivariable delirium risk prediction models and any clinical trials that examined prevention or treatment of delirium. Article titles and abstracts as well as full text articles were reviewed using Covidence software by two or more reviewers independently. Similarly, data extraction was performed by two independent reviewers. Results: A total of 21,678 titles and abstracts were screened, and 1,166 full-text articles were reviewed. Nineteen articles with varying study designs (retrospective administrative databases to clinical trials) reported on delirium using an acceptable diagnostic standard. Sample sizes varied from 15 to over 21,000. No one tumour site or treatment protocol constituted the majority of studies. The incidence of delirium ranged from 0 to 51% (mean 13.5%). The time course of delirium relative to the cycle of chemotherapy was inconsistently reported. No studies reported on risk prediction models for delirium, and no intervention studies to prevent or treat delirium were identified. An additional 109 studies reported on outcomes that could be part of the delirium syndrome but did not meet even our broad inclusion criteria (e.g. cognitive disturbance). Conclusions: Delirium may occur in over 1 in 8 older adults receiving chemotherapy, although there were substantial limitations in reported studies. This scoping review highlights the dearth of knowledge in the area, particularly for risk factors, prevention, and treatment, and emphasizes the need for high-quality studies examining these important outcomes in the oncology setting.

scholarly journals Prediction models for prostate cancer to be used in the primary care setting: a systematic review

BMJ Open ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. e034661
Author(s):  
Mohammad Aladwani ◽  
Artitaya Lophatananon ◽  
William Ollier ◽  
Kenneth Muir
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Primary Care ◽  
Community Health ◽  
Risk Prediction ◽  
Prediction Models ◽  
Risk Of Bias ◽  
Study Endpoint ◽  
Risk Prediction Models ◽  
Number Of Patients

ObjectiveTo identify risk prediction models for prostate cancer (PCa) that can be used in the primary care and community health settings.DesignSystematic review.Data sourcesMEDLINE and Embase databases combined from inception and up to the end of January 2019.EligibilityStudies were included based on satisfying all the following criteria: (i) presenting an evaluation of PCa risk at initial biopsy in patients with no history of PCa, (ii) studies not incorporating an invasive clinical assessment or expensive biomarker/genetic tests, (iii) inclusion of at least two variables with prostate-specific antigen (PSA) being one of them, and (iv) studies reporting a measure of predictive performance. The quality of the studies and risk of bias was assessed by using the Prediction model Risk Of Bias ASsessment Tool (PROBAST).Data extraction and synthesisRelevant information extracted for each model included: the year of publication, source of data, type of model, number of patients, country, age, PSA range, mean/median PSA, other variables included in the model, number of biopsy cores to assess outcomes, study endpoint(s), cancer detection, model validation and model performance.ResultsAn initial search yielded 109 potential studies, of which five met the set criteria. Four studies were cohort-based and one was a case-control study. PCa detection rate was between 20.6% and 55.8%. Area under the curve (AUC) was reported in four studies and ranged from 0.65 to 0.75. All models showed significant improvement in predicting PCa compared with being based on PSA alone. The difference in AUC between extended models and PSA alone was between 0.06 and 0.21.ConclusionOnly a few PCa risk prediction models have the potential to be readily used in the primary healthcare or community health setting. Further studies are needed to investigate other potential variables that could be integrated into models to improve their clinical utility for PCa testing in a community setting.

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