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1.
《European urology》2023,83(3):241-248
ContextProstate cancer (PCa) is a leading cause of death and partially heritable. Genetic risk prediction might be useful for strategies to reduce PCa mortality through early detection and prevention.ObjectiveTo review evidence for genetic risk prediction for PCa.Evidence acquisitionA collaborative literature review was conducted using PubMed and Google Scholar. Search terms included genetic, risk, prediction, and “prostate cancer”. Articles addressing screening, early detection, or prevention were prioritized, as were studies involving diverse populations.Evidence synthesisRare pathogenic mutations (RPMs), especially in DNA damage repair genes, increase PCa risk. RPMs in BRCA2 are most clearly deleterious, conferring 2–8.6 times higher risk of PCa and a higher risk of aggressive disease. Common genetic variants can be combined into genetic risk scores (GRSs). A high GRS (top 20–25% of the population) confers two to three times higher risk of PCa than average; a very high GRS (top 1–5%) confers six to eight times higher risk. GRSs are not specific for aggressive PCa, possibly due to methodological limitations and/or a field effect of an elevated risk for both low- and high-grade PCa. It is challenging to disentangle genetics from structural racism and social determinants of health to understand PCa racial disparities. GRSs are independently associated with a lethal PCa risk after accounting for family history and race/ancestry. Healthy lifestyle might partially mitigate the risk of lethal PCa.ConclusionsGenetic risk assessment is becoming more common; implementation studies are needed to understand the implications and to avoid exacerbating healthcare disparities. Men with a high genetic risk of PCa can reasonably be encouraged to adhere to a healthy lifestyle.Patient summaryProstate cancer risk is inherited through rare mutations and through the combination of hundreds of common genetic markers. Some men with a high genetic risk (especially BRCA2 mutations) likely benefit from early screening for prostate cancer. The risk of lethal prostate cancer can be reduced through a healthy lifestyle. 相似文献
2.
《European urology》2023,83(1):29-38
BackgroundTumor-only genomic profiling is an important tool in therapeutic management of men with prostate cancer. Since clinically actionable germline variants may be reflected in tumor profiling, it is critical to identify which variants have a higher risk of being germline in origin to better counsel patients and prioritize genetic testing.ObjectiveTo determine when variants found on tumor-only sequencing of prostate cancers should prompt confirmatory germline testing.Design, setting, and participantsMen with prostate cancer who underwent both tumor and germline sequencing at Memorial Sloan Kettering Cancer Center from January 1, 2015 to January 31, 2020 were evaluated.Outcome measurements and statistical analysisTumor and germline profiles were analyzed for pathogenic and likely pathogenic (“pathogenic”) variants in 60 moderate- or high-penetrance genes associated with cancer predisposition. The germline probability (germline/germline + somatic) of a variant was calculated for each gene. Clinical and pathologic factors were analyzed as potential modifiers of germline probability.Results and limitationsOf the 1883 patients identified, 1084 (58%) had a somatic or germline pathogenic variant in one of 60 cancer susceptibility genes, and of them, 240 (22%) had at least one germline variant. Overall, the most frequent variants were in TP53, PTEN, APC, BRCA2, RB1, ATM, and CHEK2. Variants in TP53, PTEN, or RB1 were identified in 746 (40%) patients and were exclusively somatic. Variants with the highest germline probabilities were in PALB2 (69%), MITF (62%), HOXB13 (60%), CHEK2 (55%), BRCA1 (55%), and BRCA2 (47%), and the overall germline probability of a variant in any DNA damage repair gene was 40%. Limitations were that most of the men included in the cohort had metastatic disease, and different thresholds for pathogenicity exist for somatic and germline variants.ConclusionsOf patients with pathogenic variants found on prostate tumor sequencing, 22% had clinically actionable germline variants, for which the germline probabilities varied widely by gene. Our results provide an evidenced-based clinical framework to prioritize referral to genetic counseling following tumor-only sequencing.Patient summaryPatients with advanced prostate cancer are recommended to have germline genetic testing. Genetic sequencing of a patient’s prostate tumor may also identify certain gene variants that are inherited. We found that patients who had variants in certain genes, such as ones that function in DNA damage repair, identified in their prostate tumor sequencing, had a high risk for having an inherited cancer syndrome. 相似文献
3.
《European urology》2020,77(1):24-35
BackgroundBRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies.ObjectiveTo estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.Design, setting, and participantsThis was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively).Outcome measurements and statistical analysisStandardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods.Results and limitationsSixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99–6.61) and absolute PCa risk of 27% (95% CI 17–41%) and 60% (95% CI 43–78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43–3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68–7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99–2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07–5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14–0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20–8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24–7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44–10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses.ConclusionsThe results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.Patient summaryIn this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene. 相似文献
4.
Johan Lindberg Ian G. Mills Daniel Klevebring Wennuan Liu Mårten Neiman Jianfeng Xu Pernilla Wikström Peter Wiklund Fredrik Wiklund Lars Egevad Henrik Grönberg 《European urology》2013
Background
Prostate cancer (PCa) is the most common cancer in men. PCa is strongly age associated; low death rates in surveillance cohorts call into question the widespread use of surgery, which leads to overtreatment and a reduction in quality of life. There is a great need to increase the understanding of tumor characteristics in the context of disease progression.Objective
To perform the first multigenome investigation of PCa through analysis of both autosomal and mitochondrial DNA, and to integrate exome sequencing data, and RNA sequencing and copy-number alteration (CNA) data to investigate how various different tumor characteristics, commonly analyzed separately, are interconnected.Design, setting, and participants
Exome sequencing was applied to 64 tumor samples from 55 PCa patients with varying stage and grade. Integrated analysis was performed on a core set of 50 tumors from which exome sequencing, CNA, and RNA sequencing data were available.Outcome measurements and statistical analysis
Genes, mutated at a significantly higher rate relative to a genomic background, were identified. In addition, mitochondrial and autosomal mutation rates were correlated to CNAs and proliferation, assessed as a cell cycle gene expression signature.Results and limitations
Genes not previously reported to be significantly mutated in PCa, such as cell division cycle 27 homolog (Saccharomyces cerevisiae) (CDC27), myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3), lysine (K)-specific demethylase 6A (KDM6A), and kinesin family member 5A (KIF5A) were identified. The mutation rate in the mitochondrial genome was 55 times higher than that of the autosomes. Multilevel analysis demonstrated a tight correlation between high reactive-oxygen exposure, chromosomal damage, high proliferation, and in parallel, a transition from multiclonal indolent primary PCa to monoclonal aggressive disease. As we only performed targeted sequence analysis; copy-number neutral rearrangements recently described for PCa were not accounted for.Conclusions
The mitochondrial genome displays an elevated mutation rate compared to the autosomal chromosomes. By integrated analysis, we demonstrated that different tumor characteristics are interconnected, providing an increased understanding of PCa etiology. 相似文献5.
6.
Zhuqing Shi Elizabeth A. Platz Jun Wei Rong Na Richard J. Fantus Chi-Hsiung Wang Scott E. Eggener Peter J. Hulick David Duggan S. Lilly Zheng Kathleen A. Cooney William B. Isaacs Brian T. Helfand Jianfeng Xu 《European urology》2021,79(3):419-426
BackgroundSingle nucleotide polymorphism–based genetic risk score (GRS) has been developed and validated for prostate cancer (PCa) risk assessment. As GRS is population standardized, its value can be interpreted as a relative risk to the general population.ObjectiveTo compare the performance of GRS with two guideline-recommended inherited risk measures, family history (FH) and rare pathogenic mutations (RPMs), for predicting PCa incidence and mortality.Design, setting, and participantsA prospective cohort was derived from the UK Biobank where 208 685 PCa diagnosis-free participants at recruitment were followed via the UK cancer and death registries.Outcome measurements and statistical analysisRate ratios (RRs) of PCa incidence and mortality for FH (positive vs negative), RPMs (carriers vs noncarriers), and GRS (top vs bottom quartile) were measured.Results and limitationsAfter a median follow-up of 9.67 yr, 6890 incident PCa cases (419 died of PCa) were identified. Each of the three measures was significantly associated with PCa incidence in univariate analyses; RR (95 % confidence interval [CI]) values were 1.88 (1.75–2.01) for FH, 2.89 (1.89–4.25) for RPMs, and 1.97(1.87–2.07) for GRS (all p < 0.001). The associations were independent in multivariable analyses. While FH and RPMs identified 11 % of men at higher PCa risk, addition of GRS identified an additional 22 % of men at higher PCa risk, and increases in C-statistic from 0.58 to 0.67 for differentiating incidence (p < 0.001) and from 0.65 to 0.71 for differentiating mortality (p = 0.002). Limitations were a small number of minority patients and short mortality follow-up.ConclusionsThis population-based prospective study suggests that GRS complements two guideline-recommended inherited risk measures (FH and RPMs) for stratifying the risk of PCa incidence and mortality.Patient summaryIn a large population-based prostate cancer (PCa) prospective study derived from UK Biobank, genetic risk score (GRS) complements two guideline-recommended inherited risk measures (family history and rare pathogenic mutations) in predicting PCa incidence and mortality. These results provide critical data for including GRS in PCa risk assessment. 相似文献
7.
《European urology》2014,65(5):887-894
BackgroundProstate cancer (PCa) mortality rates are lower in the Mediterranean countries compared with northern Europe. Although specific components of the Mediterranean diet (Med-Diet) may influence PCa risk, few studies have assessed the traditional Med-Diet pattern with the risk of incident advanced or lethal PCa or with disease progression among men diagnosed with nonmetastatic PCa.ObjectiveTo determine whether the traditional Med-Diet pattern is associated with risk of incident advanced or lethal PCa and with PCa-specific and overall mortality among men with PCa.Design, setting, and participantsWe prospectively followed 47 867 men in the Health Professionals Follow-up Study followed from 1986 to 2010. The case-only analysis included 4538 men diagnosed with nonmetastatic PCa, followed from diagnosis to lethal outcome or to January 2010.Outcome measurements and statistical analysisWe used Cox proportional hazards models to examine traditional and alternative Med-Diet scores in relation to PCa incidence outcomes (advanced and lethal disease). In a case-only survival analysis, we examined postdiagnostic Med-Diet and risk of lethal (metastases or PCa death) and fatal PCa as well as overall mortality among men diagnosed with nonmetastatic disease.Results and limitationsBetween 1986 and 2010, 6220 PCa cases were confirmed. The Med-Diet was not associated with risk of advanced or lethal PCa. In the case-only analysis, there was no association between the Med-Diet after diagnosis and risk of lethal or fatal PCa. However, there was a 22% lower risk of overall mortality (hazard ratio: 0.78; 95% confidence interval, 0.67–0.90; ptrend = 0.0007) among men with greater adherence to the Med-Diet after PCa diagnosis. We found similar associations for the alternative score.ConclusionsA higher Med-Diet score was not associated with risk of advanced PCa or disease progression. Greater adherence to the Med-Diet after diagnosis of nonmetastatic PCa was associated with lower overall mortality. 相似文献
8.
9.
Irene M. Shui Sara Lindström Adam S. Kibel Sonja I. Berndt Daniele Campa Travis Gerke Kathryn L. Penney Demetrius Albanes Christine Berg H. Bas Bueno-de-Mesquita Stephen Chanock E. David Crawford W. Ryan Diver Susan M. Gapstur J. Michael Gaziano Graham G. Giles Brian Henderson Robert Hoover Mattias Johansson Loic Le Marchand Jing Ma Carmen Navarro Kim Overvad Fredrick R. Schumacher Gianluca Severi Afshan Siddiq Meir Stampfer Victoria L. Stevens Ruth C. Travis Dimitrios Trichopoulos Paolo Vineis Lorelei A. Mucci Meredith Yeager Edward Giovannucci Peter Kraft 《European urology》2014
Background
Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM).Objective
To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM.Design, setting, and participants
We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred.Outcome measurements and statistical analysis
The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls.Results and limitations
Among the cases, we found that 8 of the 47 SNPs were significantly associated (p < 0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p < 0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only.Conclusions
Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa.Patient summary
In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction. 相似文献10.
Ruben G. Cremers Katja K. Aben Sita H. Vermeulen Martin den Heijer Inge M. van Oort Peter C. van de Kerkhof Jack A. Schalken Lambertus A. Kiemeney 《Urologic oncology》2014,32(7):941-945
ObjectiveSome studies have suggested an inverse association between acne vulgaris and the acne-related bacterium Propionibacterium acnes and prostate cancer (PCa). Self-reported acne might be an easily obtainable marker to identify men at relatively low risk of PCa and might be incorporated into PCa risk calculators. This study aimed to evaluate the association between self-reported acne and PCa in a large case-referent study.Methods and materialsThe case group comprised 942 patients with PCa recruited from a population-based cancer registry in 2003 to 2006, 647 of whom met the criteria for aggressive PCa. The referents (n = 2,062) were a random sample of the male general population. All subjects completed a questionnaire on risk factors for cancer, including questions about acne. Odds ratios (ORs) and 95% confidence interval (CI) were calculated using multivariable logistic regression for PCa and aggressive PCa as separate end points, while adjusting for age and family history of PCa.ResultsA history of acne was reported by 320 cases (33.9%) and 739 referents (35.8%). Self-reported acne was significantly associated neither with PCa (adjusted OR = 0.95, 95% CI: 0.80–1.12) nor with aggressive PCa (adjusted OR = 0.97, 95% CI: 0.80–1.18).ConclusionSelf-reported acne is not suitable as a marker to identify men at low risk of aggressive PCa. 相似文献
11.
ObjectivesBreast and/or ovarian cancers are complex multifactorial diseases caused by interaction of both genetic and non-genetic factors and characterized by predisposition to inheritance. BRCA1 and BRCA2 genes are the most clinically involved with these kinds of cancer and the spectrum of variants affecting these genes is very wide. In fact, point variants, large or small insertions/deletions, genomic rearrangements can be found in these patients, although a large number of variants with uncertain biological and clinical significance continues to be identified. Next-generation sequencing (NGS) technology is actually the most powerful tool for the discovering of causative mutations and novel disease genes, moreover it allows to make a rapid diagnosis of genetic variants giving fast, inexpensive and detailed genetic information.Material and methodsIn this study, we report the screening of BRCA1 and BRCA2 genes on 1400 consecutive Caucasian patients with breast and/or ovarian cancer history or family risk, attending the oncogenetic ambulatory at the Foundation Policlinico Agostino Gemelli in Rome.ResultsWe describe twenty-nine novel BRCA1 and BRCA2 variants detected in Italian individuals suffering from hereditary breast and ovarian cancer syndrome (HBOC).ConclusionData regarding novel variants can provide useful information not only at epidemiological but also at clinical level, allowing for the better managing of breast and ovarian cancer patients and their family members. 相似文献
12.
《European urology》2023,83(3):257-266
BackgroundA family history (FH) of prostate cancer (PrCa) is associated with an increased likelihood of PrCa diagnosis. Conflicting evidence exists regarding familial PrCa and clinical outcomes among PrCa patients, including all-cause mortality/overall survival (OS), PrCa-specific survival (PCSS), aggressive histology, and stage at diagnosis.ObjectiveTo determine how the number, degree, and age of a PrCa patient’s affected relatives are associated with OS and PCSS of those already diagnosed with PrCa.Design, setting, and participantsThe UK Genetic Prostate Cancer Study is a longitudinal, multi-institutional, observational study collecting baseline and follow-up clinical data since 1992. We examined OS and PCSS in 16 340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal).Outcome measurements and statistical analysisThe primary outcome was all-cause mortality among PrCa patients. The risk of death with respect to FH was assessed by calculating hazard ratios from Cox proportional hazard regression models, adjusting for relevant factors.Results and limitationsA stronger FH was inversely associated with the risk of all-cause and PrCa-specific mortality. This association was greater in those with an increasing number (p-trend < 0.001) and increasing closeness (p-trend < 0.001) of the diagnosed relatives. Patients with at least one first-degree relative were at a lower risk of all-cause mortality than those with no FH (hazard ratio = 0.82 [95% confidence interval 0.75–0.89]). The population is largely of European ancestry, and this may cause an issue with representation and generalisation. Data are missing on epidemiological risk factors for death such as smoking and on comorbidities. Recall of family members' diagnoses may affect the classification of FH in unconfirmed cases.ConclusionsBased on the investigation of the type and timing of relatives’ cancers, it is likely that reductions in mortality are due almost completely to a greater awareness of the disease. This study provides information for clinicians guiding patients and their relatives based on their familial risk. It shows the importance of screening and awareness programmes, which are likely to improve survival among men with an FH.Patient summaryWe were interested in how a family history of prostate cancer affects survival in prostate cancer patients. We studied 16 340 patients, categorised them according to the strength of their family history, and found that the stronger their family history, the better they did in terms of overall survival. We looked at the type and timing of patients’ diagnoses compared with those of their relatives and found that this effect is likely to be explained by awareness, which indicates the importance of screening and awareness programmes. 相似文献
13.
Simpa S. Salami Jeffrey J. Tosoian Srinivas Nallandhighal Tonye A. Jones Scott Brockman Fuad F. Elkhoury Selena Bazzi Komal R. Plouffe Javed Siddiqui Chia-Jen Liu Lakshmi P. Kunju Todd M. Morgan Shyam Natarajan Philip S. Boonstra Lauren Sumida Scott A. Tomlins Aaron M. Udager Anthony E. Sisk Ganesh S. Palapattu 《European urology》2021,79(4):456-465
BackgroundThe potential for low-grade (grade group 1 [GG1]) prostate cancer (PCa) to progress to high-grade disease remains unclear.ObjectiveTo interrogate the molecular and biological features of low-grade PCa serially over time.Design, setting, and participantsNested longitudinal cohort study in an academic active surveillance (AS) program. Men were on AS for GG1 PCa from 2012 to 2017.InterventionElectronic tracking and resampling of PCa using magnetic resonance imaging/ultrasound fusion biopsy.Outcome measurements and statistical analysisERG immunohistochemistry (IHC) and targeted DNA/RNA next-generation sequencing were performed on initial and repeat biopsies. Tumor clonality was assessed. Molecular data were compared between men who upgraded and those who did not upgrade to GG ≥ 2 cancer.Results and limitationsSixty-six men with median age 64 yr (interquartile range [IQR], 59–69) and prostate-specific antigen 4.9 ng/mL (IQR, 3.3–6.4) underwent repeat sampling of a tracked tumor focus (median interval, 11 mo; IQR, 6–13). IHC-based ERG fusion status was concordant at initial and repeat biopsies in 63 men (95% vs expected 50%, p < 0.001), and RNAseq-based fusion and isoform expression were concordant in nine of 13 (69%) ERG+ patients, supporting focal resampling. Among 15 men who upgraded with complete data at both time points, integrated DNA/RNAseq analysis provided evidence of shared clonality in at least five cases. Such cases could reflect initial undersampling, but also support the possibility of clonal temporal progression of low-grade cancer. Our assessment was limited by sample size and use of targeted sequencing.ConclusionsRepeat molecular assessment of low-grade tumors suggests that clonal progression could be one mechanism of upgrading. These data underscore the importance of serial tumor assessment in men pursuing AS of low-grade PCa.Patient summaryWe performed targeted rebiopsy and molecular testing of low-grade tumors on active surveillance. Our findings highlight the importance of periodic biopsy as a component of monitoring for cancer upgrading during surveillance. 相似文献
14.
Vito Cucchiara Matthew R. Cooperberg Marc Dall’Era Daniel W. Lin Francesco Montorsi Jack A. Schalken Christopher P. Evans 《European urology》2018,73(4):572-582
Context
Although the widespread use of prostate-specific antigen (PSA) has led to an early detection of prostate cancer (PCa) and a reduction of metastatic disease at diagnosis, PSA remains one of the most controversial biomarkers due to its limited specificity. As part of emerging efforts to improve both detection and management decision making, a number of new genomic tools have recently been developed.Objective
This review summarizes the ability of genomic biomarkers to recognize men at high risk of developing PCa, discriminate clinically insignificant and aggressive tumors, and facilitate the selection of therapies in patients with advanced disease.Evidence acquisition
A PubMed-based literature search was conducted up to May 2017. We selected the most recent and relevant original articles and clinical trials that have provided indispensable information to guide treatment decisions.Evidence synthesis
Genome-wide association studies have identified several genetic polymorphisms and inherited variants associated with PCa susceptibility. Moreover, the urine-based assays SelectMDx, Mi-Prostate Score, and ExoDx have provided new insights into the identification of patients who may benefit from prostate biopsy. In men with previous negative pathological findings, Prostate Cancer Antigen 3 and ConfirmMDx predicted the outcome of subsequent biopsy. Commercially available tools (Decipher, Oncotype DX, and Prolaris) improved PCa risk stratification, identifying men at the highest risk of adverse outcome. Furthermore, other biomarkers could assist in treatment selection in castration-resistant PCa. AR-V7 expression predicts resistance to abiraterone/enzalutamide, while poly(ADP-ribose) polymerase-1 inhibitor and platinum-based chemotherapy could be indicated in metastatic patients who are carriers of mutations in DNA mismatch repair genes.Conclusions
Introduction of genomic biomarkers has dramatically improved the detection, prognosis, and risk evaluation of PCa. Despite the progress made in discovering suitable biomarker candidates, few have been used in a clinical setting. Large-scale and multi-institutional studies are required to validate the efficacy and cost utility of these new technologies.Patient summary
Prostate cancer is a heterogeneous disease with a wide variability. Genomic biomarkers in combination with clinical and pathological variables are useful tools to reduce the number of unnecessary biopsies, stratify low-risk from high-risk tumors, and guide personalized treatment decisions. 相似文献15.
Eric A. Klein Matthew R. Cooperberg Cristina Magi-Galluzzi Jeffry P. Simko Sara M. Falzarano Tara Maddala June M. Chan Jianbo Li Janet E. Cowan Athanasios C. Tsiatis Diana B. Cherbavaz Robert J. Pelham Imelda Tenggara-Hunter Frederick L. Baehner Dejan Knezevic Phillip G. Febbo Steven Shak Michael W. Kattan Mark Lee Peter R. Carroll 《European urology》2014
16.
《Urologic oncology》2020,38(3):80.e1-80.e7
BackgroundProstate cancer is among the most heritable cancers, and clinical testing for germline genetic variants based on ethnicity, disease features, and family history has recently become standard of care for men with advanced disease. It is not established whether prevalence of germline variants varies based on ethnicity or race.MethodsWe retrospectively examined germline genetic and clinical data of men reporting a diagnosis of prostate cancer referred to Color Genomics by a healthcare provider for testing of 30 genes associated with hereditary cancer risk. Variants were classified as pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign, or benign. P/LP and VUS prevalence was compared among subgroups classified by age at diagnosis, self-reported ethnicity, family history, and history of other cancer.ResultsWe identified 1,351 men reporting a diagnosis of prostate cancer of any stage who underwent germline testing. Overall, 78% of men were Caucasian, 11% Ashkenazi Jewish, 3% African-American/Canadian (AAC), 2% Hispanic, 2% Asian/Pacific Islander (API), and 4% Other (multiple, unknown, Native-American). One-hundred eighty-seven men (13.8%) carried a P/LP variant, and the most prevalent P/LP variants were in BRCA2 (3.4%), CHEK2 (2.8%), MUTYH (1.8%), and ATM (1.7%). Age at diagnosis, ethnicity, type of family member with prostate cancer, and type of second cancer were not associated with risk of carrying any P/LP variant. Ashkenazi Jewish men (6.7%) were more likely to carry P/LP BRCA2 variants than Caucasian men (2.8%) (P < 0.05). Two-hundred eighty-four men (21.0%) carried a VUS, and AAC (36.6%) and API (33.3%) men were most likely to carry a VUS (P < 0.01).ConclusionsP/LP germline variants are prevalent in men with prostate cancer. AAC, Hispanic, and API men with prostate cancer are under-represented in studies of germline testing, potentially contributing to higher rates of VUS relative to Caucasian and Ashkenazi Jewish men. Further studies in these groups will facilitate reclassification of VUS, increasing opportunities for early detection, cancer risk modification, and targeted therapeutics. 相似文献
17.
Tommy Nyberg Koveela Govindasami Goska Leslie Tokhir Dadaev Elizabeth Bancroft Holly Ni Raghallaigh Mark N. Brook Nafisa Hussain Diana Keating Andrew Lee Romayne McMahon Angela Morgan Andrea Mullen Andrea Osborne Reshma Rageevakumar Zsofia Kote-Jarai Rosalind Eeles Antonis C. Antoniou 《European urology》2019,75(5):834-845
Background
The homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain.Objective
To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors.Design, setting, and participants
Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11 983 PCa patients enrolled during 1993–2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E.Outcome measurements and statistical analysis
Relative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort.Results and limitations
A meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95–33.0, p < 0.001) and differences by case selection (p = 0.007). Based on case-control studies unselected for PCa family history, the pooled RR estimate was 3.43 (95% confidence interval [CI] 2.78–4.23). In the kin-cohort study, PCa risk for mutation carriers varied by family history (p < 0.001). There was a suggestion that RRs decrease with age, but this was not significant (p = 0.068). We found higher RR estimates for men from more recent birth cohorts (p = 0.004): 3.09 (95% CI 2.03–4.71) for men born in 1929 or earlier and 5.96 (95% CI 4.01–8.88) for men born in 1930 or later. The absolute PCa risk by age 85 for a male HOXB13 G84E carrier varied from 60% for those with no PCa family history to 98% for those with two relatives diagnosed at young ages, compared with an average risk of 15% for noncarriers. Limitations include the reliance on self-reported cancer family history.Conclusions
PCa risks for HOXB13 G84E mutation carriers are heterogeneous. Counselling should not be based on average risk estimates but on age-specific absolute risk estimates tailored to individual mutation carriers’ family history and birth cohort.Patient summary
Men who carry a hereditary mutation in the homeobox B13 (HOXB13) gene have a higher than average risk for developing prostate cancer. In our study, we examined a large number of families of men with prostate cancer recruited across UK hospitals, to assess what other factors may contribute to this risk and to assess whether we could create a precise model to help in predicting a man's prostate cancer risk. We found that the risk of developing prostate cancer in men who carry this genetic mutation is also affected by a family history of prostate cancer and their year of birth. This information can be used to assess more personalised prostate cancer risks to men who carry HOXB13 mutations and hence better counsel them on more personalised risk management options, such as tailoring prostate cancer screening frequency. 相似文献18.
《European urology》2014,65(4):816-824
BackgroundAndrogen-deprivation therapy (ADT) for prostate cancer (PCa) is associated with decreased insulin sensitivity and increased diabetes risk among nondiabetic men. Few data are available about the effects of ADT on diabetes control among men with diabetes.ObjectiveWe examined care for men who had diabetes at the time of PCa diagnosis to assess the effect of ADT on diabetes control, as measured by hemoglobin A1c (HbA1c) levels and the intensification of diabetes pharmacotherapy.Design, setting, and participantsThis was an observational cohort study using US Department of Veterans Affairs registry data and administrative data to assess HbA1c levels and intensification of diabetes pharmacotherapy among 2237 pairs of propensity-matched men with PCa and diabetes who were or were not treated with ADT.Outcome measurements and statistical analysisWe calculated the difference in difference of HbA1c levels at baseline and at 1 and 2 yr in the two groups, compared using a paired Student t test. We used a Cox proportional hazards model to estimate time to intensification of diabetes pharmacotherapy.Results and limitationsThe mean HbA1c at baseline was 7.24 (standard error [SE]: 0.05) for the ADT group and 7.24 (SE: 0.04) for the no-ADT group. HbA1c increased at 1 yr for men treated with ADT to 7.38 (SE: 0.04) and decreased among men not treated with ADT to 7.14 (SE: 0.04), for a difference in differences of +0.24 (p = 0.008). Results were similar at 2 yr (p = 0.03). The worsening HbA1c control occurred despite ADT being associated with an increased hazard of addition of diabetes medication (adjusted hazard ratio: 1.20; 95% confidence interval, 1.09–1.32). The limitation of this study was that it was observational and relied on administrative data.ConclusionsADT is associated with worsening of diabetes control and increases in HbA1c levels despite the use of additional diabetes medications. 相似文献
19.
John J. Bauer Shiv Srivastava Roger R. Connelly Isabell A. Sesterhenn David M. Preston David G. McLeod Judd W. Moul 《Urology》1998,51(6):970-976
Objectives. Prostate cancer (PCa) has a familial predisposition imparting an increased risk of developing the disease in those with a family history. The pathologic characteristics are similar to sporadic cases; however, the disease-free survival rates of hereditary PCa have recently been disputed, with one major study suggesting that familial cases have higher recurrence rates. Our study seeks to support or refute this association and to evaluate the genetic biomarkers p53, bcl-2, Ki-67, and neovascularity between familial and sporadic disease.Methods. We retrospectively reviewed data of 573 patients who underwent radical prostatectomy over an 11-year period. Of these, 474 patients had known family history data. Univariable statistical analysis using the Pearson chi-square test and Kaplan-Meier disease-free survival analysis was performed to identify any correlation between the tested variables and family history. Smaller subsets of this cohort that had available archival material for immunohistochemical staining and family history data were analyzed in a similar manner.Results. The preoperative variables (prostate-specific antigen, prostatic acid phosphatase, clinical stage, highest biopsy Gleason sum, and glandular differentiation) and postoperative variables (stage, highest Gleason sum, and glandular differentiation) did not correlate with family history. Kaplan-Meier disease-free survival analysis revealed no differences between sporadic and familial cases. The analysis of p53, bcl-2, Ki-67, and angiogenesis revealed that only increasing p53 expression and positive family history of PCa approached significance (P = 0.057).Conclusions. Prognostic variables routinely used in PCa and selected genetic biomarker immunostaining abnormalities are not significantly different in men with and without a family history of PCa. Disease-free survival after radical prostatectomy is also unaffected by family history. 相似文献
20.
Audet-Walsh É Bellemare J Lacombe L Fradet Y Fradet V Douville P Guillemette C Lévesque É 《European urology》2012,62(1):88-96