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1.
Int J Mol Sci ; 25(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38731833

RESUMO

This two-sample Mendelian randomization (MR) study was conducted to investigate the causal associations between type 2 diabetes mellitus (T2DM) and the risk of pancreatic cancer (PaCa), as this causal relationship remains inconclusive in existing MR studies. The selection of instrumental variables for T2DM was based on two genome-wide association study (GWAS) meta-analyses from European cohorts. Summary-level data for PaCa were extracted from the FinnGen and UK Biobank databases. Inverse variance weighted (IVW) and four other robust methods were employed in our MR analysis. Various sensitivity analyses and multivariable MR approaches were also performed to enhance the robustness of our findings. In the IVW and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analyses, the odds ratios (ORs) for each 1-unit increase in genetically predicted log odds of T2DM were approximately 1.13 for PaCa. The sensitivity tests and multivariable MR supported the causal link between T2DM and PaCa without pleiotropic effects. Therefore, our analyses suggest a causal relationship between T2DM and PaCa, shedding light on the potential pathophysiological mechanisms of T2DM's impact on PaCa. This finding underscores the importance of T2DM prevention as a strategy to reduce the risk of PaCa.


Assuntos
Diabetes Mellitus Tipo 2 , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Neoplasias Pancreáticas , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/epidemiologia , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Razão de Chances , Fatores de Risco
2.
Eur Urol Oncol ; 7(2): 248-257, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38458890

RESUMO

BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Próstata/patologia , Genes BRCA2 , Mutação
3.
Biomedicines ; 11(12)2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-38137427

RESUMO

Pancreatic cancer (PaCa) is a lethal cancer with an increasing incidence, highlighting the need for early prevention strategies. There is a lack of a comprehensive PaCa predictive model derived from large prospective cohorts. Therefore, we have developed an integrated PaCa risk prediction model for PaCa using data from the UK Biobank, incorporating lifestyle-related, genetic-related, and medical history-related variables for application in healthcare settings. We used a machine learning-based random forest approach and a traditional multivariable logistic regression method to develop a PaCa predictive model for different purposes. Additionally, we employed dynamic nomograms to visualize the probability of PaCa risk in the prediction model. The top five influential features in the random forest model were age, PRS, pancreatitis, DM, and smoking. The significant risk variables in the logistic regression model included male gender (OR = 1.17), age (OR = 1.10), non-O blood type (OR = 1.29), higher polygenic score (PRS) (Q5 vs. Q1, OR = 2.03), smoking (OR = 1.82), alcohol consumption (OR = 1.27), pancreatitis (OR = 3.99), diabetes (DM) (OR = 2.57), and gallbladder-related disease (OR = 2.07). The area under the receiver operating curve (AUC) of the logistic regression model is 0.78. Internal validation and calibration performed well in both models. Our integrative PaCa risk prediction model with the PRS effectively stratifies individuals at future risk of PaCa, aiding targeted prevention efforts and supporting community-based cancer prevention initiatives.

4.
Nat Genet ; 55(12): 2065-2074, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37945903

RESUMO

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.


Assuntos
Predisposição Genética para Doença , Neoplasias da Próstata , Humanos , Masculino , População Negra/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Fatores de Risco , População Branca/genética , Povo Asiático/genética
5.
J Clin Urol ; 16(4): 264-273, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37614642

RESUMO

Introduction: Modern image-guided biopsy pathways at diagnostic centres have greatly refined the investigations of men referred with suspected prostate cancer. However, the referral criteria from primary care are still based on historical prostate-specific antigen (PSA) cut-offs and age-referenced thresholds. Here, we tested whether better contemporary pathways and biopsy methods had improved the predictive utility value of PSA referral thresholds. Methods: PSA referral thresholds, age-referenced ranges and PSA density (PSAd) were assessed for positive predictive value (PPV) in detection of clinically significant prostate cancer (csPCa - histological ⩾ Grade Group 2). Data were analysed from men referred to three diagnostics centres who used multi-parametric magnetic resonance imaging (mpMRI)-guided prostate biopsies for disease characterisation. Findings were validated in a separate multicentre cohort. Results: Data from 2767 men were included in this study. The median age, PSA and PSAd were 66.4 years, 7.3 ng/mL and 0.1 ng/mL2, respectively. Biopsy detected csPCa was found in 38.7%. The overall area under the curve (AUC) for PSA was 0.68 which is similar to historical performance. A PSA threshold of ⩾ 3 ng/mL had a PPV of 40.3%, but this was age dependent (PPV: 24.8%, 32.7% and 56.8% in men 50-59 years, 60-69 years and ⩾ 70 years, respectively). Different PSA cut-offs and age-reference ranges failed to demonstrate better performance. PSAd demonstrated improved AUC (0.78 vs 0.68, p < 0.0001) and improved PPV compared to PSA. A PSAd of ⩾ 0.10 had a PPV of 48.2% and similar negative predictive value (NPV) to PSA ⩾ 3 ng/mL and out-performed PSA age-reference ranges. This improved performance was recapitulated in a separate multi-centre cohort (n = 541). Conclusion: The introduction of MRI-based image-guided biopsy pathways does not appear to have altered PSA diagnostic test characteristics to positively detect csPCa. We find no added value to PSA age-referenced ranges, while PSAd offers better PPV and the potential for a single clinically useful threshold (⩾0.10) for all age groups. Level of evidence: IV.

6.
Genet Med ; 25(9): 100898, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37212253

RESUMO

PURPOSE: A third of familial epithelial ovarian cancer (EOC) is explained by BRCA1/2 pathogenic variants. Polygenic risk scores (PRSs) for BRCA1/2 heterozygotes associated with EOC have been created, but impact of combination with clinical and hormonal risk factors is unclear. METHODS: We genotyped 300 cases and 355 controls and constructed modified PRSs based on those validated by Barnes et al. Model discrimination and EOC risk was assessed by area under the curve (AUC) values and difference between lowest and highest quintile odds ratios (ORs). We investigated model optimization using logistic regression to combine models with clinical and hormonal data. RESULTS: Unadjusted AUC values ranged from 0.526 to 0.551 with 2.2- to 2.3-fold increase in OR between lowest and highest quintiles (BRCA1 heterozygotes) and 0.574 to 0.585 AUC values with a 6.3- to 7.7-fold increase (BRCA2 heterozygotes). The optimized model (parity, age at menarche, menopause, and first full-term pregnancy) estimated AUC values of 0.872 to 0.876 and 21- to 23-fold increase in OR (BRCA1 heterozygotes) and AUC values of 0.857 to 0.867 and 40- to 41-fold increase (BRCA2 heterozygotes). CONCLUSION: The combination of PRS with age, family history, and hormonal factors significantly improved the EOC risk discrimination ability. However, the contribution of the PRS was small. Larger prospective studies are needed to assess if combined-PRS models could provide information to inform risk-reducing decisions.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Gravidez , Humanos , Feminino , Proteína BRCA1/genética , Heterozigoto , Carcinoma Epitelial do Ovário/genética , Predisposição Genética para Doença , Proteína BRCA2/genética , Fatores de Risco , Neoplasias Ovarianas/genética
7.
J Clin Oncol ; 41(5): 1092-1104, 2023 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-36493335

RESUMO

PURPOSE: Prostate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort. MATERIALS AND METHODS: We developed a risk model using a kin-cohort comprising individuals from 16,633 PCa families ascertained in the United Kingdom from 1993 to 2017 from the UK Genetic Prostate Cancer Study, and complex segregation analysis adjusting for ascertainment. The model was externally validated in 170,850 unaffected men (7,624 incident PCas) recruited from 2006 to 2010 to the independent UK Biobank prospective cohort study. RESULTS: The most parsimonious model included the effects of pathogenic variants in BRCA2, HOXB13, and BRCA1, and a polygenic score on the basis of 268 common low-risk variants. Residual familial risk was modeled by a hypothetical recessively inherited variant and a polygenic component whose standard deviation decreased log-linearly with age. The model predicted familial risks that were consistent with those reported in previous observational studies. In the validation cohort, the model discriminated well between unaffected men and men with incident PCas within 5 years (C-index, 0.790; 95% CI, 0.783 to 0.797) and 10 years (C-index, 0.772; 95% CI, 0.768 to 0.777). The 50% of men with highest predicted risks captured 86.3% of PCa cases within 10 years. CONCLUSION: To our knowledge, this is the first validated risk model offering personalized PCa risks. The model will assist in counseling men concerned about their risk and can facilitate future risk-stratified population screening approaches.


Assuntos
Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Estudos Prospectivos , Neoplasias da Próstata/patologia , Antígeno Prostático Específico , Fatores de Risco
8.
Eur Urol ; 83(3): 257-266, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36528478

RESUMO

BACKGROUND: A 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. OBJECTIVE: To 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 PARTICIPANTS: The 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 16340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The 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 LIMITATIONS: A 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. CONCLUSIONS: Based 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 SUMMARY: We were interested in how a family history of prostate cancer affects survival in prostate cancer patients. We studied 16340 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.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Neoplasias da Próstata/diagnóstico , Antígeno Prostático Específico , Próstata/patologia , Fatores de Risco , Reino Unido/epidemiologia
9.
Am J Hum Genet ; 109(12): 2185-2195, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36356581

RESUMO

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.


Assuntos
Neoplasias da Mama , Estudo de Associação Genômica Ampla , Feminino , Humanos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles
10.
Cancers (Basel) ; 14(20)2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36291775

RESUMO

Evidence on pancreatic cancer (PaCa) risk factors from large population-based cohort studies is limited. This study investigated the PaCa risk factors and the population attributable fraction (PAF) of modifiable risk factors in the UK Biobank cohort. The UK Biobank is a prospective cohort consisting of 502,413 participants with a mean follow-up time of 8.2 years. A binomial generalized linear regression model was used to calculate relative risks for PaCa risk factors. PAF was calculated to estimate the proportional reduction in PaCa if modifiable risk factors were to be eliminated. A total of 728 (0.14%) PaCa incident cases and 412,922 (82.19%) non-PaCa controls were analyzed. The non-modifiable risk factors included age and gender. The modifiable risk factors were cigarette smoking, overweight and obesity, increased waist circumstance, abdominal obesity, Diabetic Mellitus (DM), and pancreatitis history. The PAF suggested that eliminating smoking and obesity can contribute around a 16% reduction in PaCa cases while avoiding abdominal obesity can eliminate PaCa cases by 22%. Preventing pancreatitis and DM could potentially reduce PaCa cases by 1% and 6%, respectively. This study has identified modifiable and non-modifiable PaCa risk factors in the UK population. The PAF of modifiable risk factors can be applied to inform PaCa prevention programs.

11.
BMC Cancer ; 22(1): 878, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953766

RESUMO

INTRODUCTION: Pre-treatment risk and prognostic groups are the cornerstone for deciding management in non-metastatic prostate cancer. All however, were developed in the pre-MRI era. Here we compared categorisation of cancers using either only clinical parameters or with MRI enhanced information in men referred for suspected prostate cancer from an unscreened population. PATIENT AND METHODS: Data from men referred from primary care to our diagnostic service and with both clinical (digital rectal examination [DRE] and systematic biopsies) and MRI enhanced attributes (MRI stage and combined systematic/targeted biopsies) were used for this study. Clinical vs MRI data were contrasted for clinico-pathological and risk group re-distribution using the European Association of Urology (EAU), American Urological Association (AUA) and UK National Institute for Health Care Excellence (NICE) Cambridge Prognostic Group (CPG) models. Differences were retrofitted to a population cohort with long-term prostate cancer mortality (PCM) outcomes to simulate impact on model performance. We further contrasted individualised overall survival (OS) predictions using the Predict Prostate algorithm. RESULTS: Data from 370 men were included (median age 66y). Pre-biopsy MRI stage reassignments occurred in 7.8% (versus DRE). Image-guided biopsies increased Grade Group 2 and ≥ Grade Group 3 assignments in 2.7% and 2.9% respectively. The main change in risk groups was more high-risk cancers (6.2% increase in the EAU and AUA system, 4.3% increase in CPG4 and 1.9% CPG5). When extrapolated to a historical population-based cohort (n = 10,139) the redistribution resulted in generally lower concordance indices for PCM. The 5-tier NICE-CPG system outperformed the 4-tier AUA and 3-tier EAU models (C Index 0.70 versus 0.65 and 0.64). Using an individualised prognostic model, changes in predicted OS were small (median difference 1% and 2% at 10- and 15-years' respectively). Similarly, estimated treatment survival benefit changes were minimal (1% at both 10- and 15-years' time frame). CONCLUSION: MRI guided diagnostics does change pre-treatment risk groups assignments but the overall prognostic impact appears modest in men referred from unscreened populations. Particularly, when using more granular tiers or individualised prognostic models. Existing risk and prognostic models can continue to be used to counsel men about treatment option until long term survival outcomes are available.


Assuntos
Neoplasias da Próstata , Idoso , Humanos , Biópsia Guiada por Imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Prognóstico , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/terapia
12.
Genet Med ; 24(9): 1847-1856, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35704044

RESUMO

PURPOSE: Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention. METHODS: We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB). RESULTS: Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, Ptrend = 5.75E-9). Combining PRS19 with age and body mass index improved discriminatory power (Manchester study: AUC = 0.79, 95% CI = 0.76-0.82; UKBB: AUC =0.75, 95% CI = 0.73-0.76). CONCLUSION: An endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.


Assuntos
Neoplasias do Endométrio , Herança Multifatorial , Feminino , Humanos , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Medição de Risco , Fatores de Risco
13.
Cancer Prev Res (Phila) ; 15(9): 605-621, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35696722

RESUMO

Endometrial cancer incidence is rising, with 435,000 global cases in 2019. An effective, low-cost primary prevention strategy is required to reduce disease burden. Obesity, insulin resistance, and inflammation contribute to endometrial carcinogenesis and physical activity targets these pathways. This study sought to quantify the amount of physical activity required to impact upon endometrial cancer risk. Physical activity data from 222,031 female participants with an intact uterus in the UK Biobank study were analyzed using a multivariable Cox proportional hazards model. A systematic review of the literature was performed, searching CENTRAL, Embase, and MEDLINE databases up to April 19, 2021. Studies including participants with and without endometrial cancer investigating the effect of physical activity measured in MET-hours/week (MET-h/week) on disease risk were included. Two reviewers independently selected studies, extracted data, and evaluated the risk of bias. Within the UK Biobank, each 1 MET-h/week increase in total physical activity was associated with a 0.2% [95% confidence interval (CI), 0.1-0.4; P = 0.020] reduction in endometrial cancer risk, equating to a 10.4% reduction if performing 50 MET-h/week or 7 hours of jogging per week. Eleven cohort and 12 case-control studies were identified in the systematic review, including 821,599 participants. One study reported a nonsignificant effect of 1 MET-h/week increases in physical activity on endometrial cancer risk (OR, 1.00; 95% CI, 0.99-1.00). Eight studies found significant reductions in disease risk of 15%-53%, but only in the most physically active individuals. Physical activity reduces endometrial cancer risk, but the effect size appears small. Regular vigorous activity should be encouraged to maximize the health benefit observed. PREVENTION RELEVANCE: Effective, low-cost primary prevention strategies are urgently needed to tackle the rapid global increase in endometrial cancer. We sought to quantify the effect of physical activity on endometrial cancer risk, noting a linear inverse relationship influenced by body mass index. The most beneficial type and amount of activity remain unclear.


Assuntos
Neoplasias do Endométrio , Exercício Físico , Índice de Massa Corporal , Estudos de Coortes , Neoplasias do Endométrio/complicações , Neoplasias do Endométrio/epidemiologia , Neoplasias do Endométrio/prevenção & controle , Feminino , Humanos , Obesidade/complicações
14.
Breast Cancer ; 29(5): 869-879, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35543923

RESUMO

BACKGROUND: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. METHODS: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. RESULTS: We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). CONCLUSIONS: No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.


Assuntos
Neoplasias da Mama , Antígenos HLA , Alelos , Povo Asiático/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA/genética , Humanos , Polimorfismo de Nucleotídeo Único
15.
Prostate Cancer Prostatic Dis ; 25(4): 755-761, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35152271

RESUMO

BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Antígeno Prostático Específico/genética , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Detecção Precoce de Câncer , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Medição de Risco , Predisposição Genética para Doença
16.
J Clin Med ; 12(1)2022 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-36615017

RESUMO

For men with newly diagnosed prostate cancer, we aimed to develop and validate a model to predict the risk of progression on active surveillance (AS), which could inform more personalised AS strategies. In total, 883 men from 3 European centres were used for model development and internal validation, and 151 men from a fourth European centre were used for external validation. Men with Cambridge Prognostic Group (CPG) 1-2 disease at diagnosis were eligible. The endpoint was progression to the composite endpoint of CPG3 disease or worse (≥CPG3). Model performance at 4 years was evaluated through discrimination (C-index), calibration plots, and decision curve analysis. The final multivariable model incorporated prostate-specific antigen (PSA), Grade Group, magnetic resonance imaging (MRI) score (Prostate Imaging Reporting & Data System (PI-RADS) or Likert), and prostate volume. Calibration and discrimination were good in both internal validation (C-index 0.742, 95% CI 0.694-0.793) and external validation (C-index 0.845, 95% CI 0.712-0.958). In decision curve analysis, the model offered net benefit compared to a 'follow-all' strategy at risk thresholds of ≥0.08 and ≥0.04 in development and external validation, respectively. In conclusion, our model demonstrated good accuracy and clinical utility in predicting the progression on AS at 4 years post-diagnosis. Men with lower risk predictions could subsequently be offered less-intense surveillance. Further external validation in larger cohorts is now required.

17.
Genet Med ; 24(3): 586-600, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34906514

RESUMO

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.


Assuntos
Neoplasias da Mama , Teorema de Bayes , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Fatores de Risco
18.
Prostate Cancer Prostatic Dis ; 25(2): 229-237, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34127801

RESUMO

BACKGROUND: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. MATERIALS AND METHODS: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. RESULTS: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. CONCLUSION: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.


Assuntos
População Negra , Cromossomos Humanos Par 8 , Predisposição Genética para Doença , Herança Multifatorial , Neoplasias da Próstata , População Negra/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/genética , Medição de Risco , População Branca/genética
19.
Prostate Cancer Prostatic Dis ; 24(3): 845-851, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33723363

RESUMO

BACKGROUND: Clinical variables-age, family history, genetics-are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death. METHODS: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n = 3279; 2163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests. RESULTS: Median age at last follow-up/prostate cancer death was 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p < 10-15). CONCLUSIONS: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Neoplasias da Próstata/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Prognóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Taxa de Sobrevida , Suécia/epidemiologia
20.
Prostate Cancer Prostatic Dis ; 24(2): 532-541, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.


Assuntos
Biomarcadores Tumorais/genética , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Medição de Risco/métodos , Adulto , Idoso , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Fatores de Risco
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