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1.
Cancer Res ; 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558336

RESUMO

Insights into oncogenesis derived from cancer susceptibility loci (single nucleotide polymorphisms, SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, while both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of pro-survival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacological inhibition of the pro-survival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies.

2.
BMC Med ; 18(1): 327, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33198768

RESUMO

BACKGROUND: Observational studies have investigated the association of risk factors with breast cancer prognosis. However, the results have been conflicting and it has been challenging to establish causality due to potential residual confounding. Using a Mendelian randomisation (MR) approach, we aimed to examine the potential causal association between breast cancer-specific survival and nine established risk factors for breast cancer: alcohol consumption, body mass index, height, physical activity, mammographic density, age at menarche or menopause, smoking, and type 2 diabetes mellitus (T2DM). METHODS: We conducted a two-sample MR analysis on data from the Breast Cancer Association Consortium (BCAC) and risk factor summary estimates from the GWAS Catalog. The BCAC data included 86,627 female patients of European ancestry with 7054 breast cancer-specific deaths during 15 years of follow-up. Of these, 59,378 were estrogen receptor (ER)-positive and 13,692 were ER-negative breast cancer patients. For the significant association, we used sensitivity analyses and a multivariable MR model. All risk factor associations were also examined in a model adjusted by other prognostic factors. RESULTS: Increased genetic liability to T2DM was significantly associated with worse breast cancer-specific survival (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.03-1.17, P value [P] = 0.003). There were no significant associations after multiple testing correction for any of the risk factors in the ER-status subtypes. For the reported significant association with T2DM, the sensitivity analyses did not show evidence for violation of the MR assumptions nor that the association was due to increased BMI. The association remained significant when adjusting by other prognostic factors. CONCLUSIONS: This extensive MR analysis suggests that T2DM may be causally associated with worse breast cancer-specific survival and therefore that treating T2DM may improve prognosis.

3.
Gynecol Oncol ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33246661

RESUMO

OBJECTIVE: Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and survival in this group remains poor. Circulating proteins associated with the risk of developing EOC have the potential to serve as biomarkers for early detection and diagnosis. We integrated large-scale genomic and proteomic data to identify novel plasma proteins associated with EOC risk. METHODS: We used the germline genetic variants most strongly associated (P <1.5 × 10-11) with plasma levels of 1329 proteins in 3301 healthy individuals from the INTERVAL study to predict circulating levels of these proteins in 22,406 EOC cases and 40,941 controls from the Ovarian Cancer Association Consortium (OCAC). Association testing was performed by weighting the beta coefficients and standard errors for EOC risk from the OCAC study by the inverse of the beta coefficients from INTERVAL. RESULTS: We identified 26 proteins whose genetically predicted circulating levels were associated with EOC risk at false discovery rate < 0.05. The 26 proteins included MFAP2, SEMG2, DLK1, and NTNG1 and a group of 22 proteins whose plasma levels were predicted by variants at chromosome 9q34.2. All 26 protein association signals identified were driven by association with the high-grade serous histotype that comprised 58% of the EOC cases in OCAC. Regional genomic plots confirmed overlap of the genetic association signal underlying both plasma protein level and EOC risk for the 26 proteins. Pathway analysis identified enrichment of seven biological pathways among the 26 proteins (Padjusted <0.05), highlighting roles for Focal Adhesion-PI3K-Akt-mTOR and Notch signaling. CONCLUSION: The identified proteins further illuminate the etiology of EOC and represent promising new EOC biomarkers for targeted validation by studies involving direct measurement of plasma proteins in EOC patient cohorts.

4.
Nat Genet ; 52(11): 1219-1226, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33106634

RESUMO

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

5.
Am J Hum Genet ; 107(5): 837-848, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022221

RESUMO

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

6.
J Natl Cancer Inst ; 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32766851

RESUMO

BACKGROUND: Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. METHODS: A pooled analysis of 10,470 invasive epithelial ovarian cancer cases and 16,942 controls was conducted. Odds ratios and 95% confidence intervals for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race/ethnicity, age, and education level, and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. RESULTS: Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (two-sided Ptrend <.001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. CONCLUSIONS: Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

7.
Mod Pathol ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724153

RESUMO

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

8.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.

10.
Breast Cancer Res Treat ; 181(2): 423-434, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279280

RESUMO

BACKGROUND: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). METHODS: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. RESULTS: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. CONCLUSIONS: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.


Assuntos
Neoplasias da Mama/patologia , Tomada de Decisão Clínica , Segunda Neoplasia Primária/patologia , Medição de Risco/métodos , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Agências Internacionais , Mastectomia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/cirurgia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Fatores de Risco
11.
Cancer Med ; 9(10): 3563-3573, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32207560

RESUMO

BACKGROUND: Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. METHODS: To improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. RESULTS: Among 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10-5 ), PSMC5 (P = 4.51 × 10-4 ) and CD33 (P = 2.71 × 10-4 ) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10-5 ) and SCN1B (P = 2.76 × 10-4 ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10-5 ). CONCLUSIONS: Aggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

12.
Cancer Epidemiol Biomarkers Prev ; 29(4): 860-870, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32051193

RESUMO

BACKGROUND: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. METHODS: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. RESULTS: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93-0.98; P = 5.2 × 10-4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92-0.97; P = 5.4 × 10-5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03-1.08; P = 3.3 × 10-5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01-1.07; P = 2.5 × 10-3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01-1.06; P = 1.2 × 10-2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. CONCLUSIONS: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. IMPACT: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

13.
J Natl Cancer Inst ; 112(3): 295-304, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31143935

RESUMO

BACKGROUND: DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. METHODS: Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women's Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. RESULTS: Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10-7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. CONCLUSION: Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Grupo com Ancestrais do Continente Europeu/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Ilhas de CpG , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Risco , Transcriptoma
14.
Int J Epidemiol ; 49(1): 216-232, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605532

RESUMO

BACKGROUND: Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication of previously reported interactions. METHODS: Analyses were performed using 28 176 cases and 32 209 controls genotyped with iCOGS array and 44 109 cases and 48 145 controls genotyped using OncoArray from the Breast Cancer Association Consortium (BCAC). Gene-environment interactions were assessed using unconditional logistic regression and likelihood ratio tests for breast cancer risk overall and by estrogen-receptor (ER) status. Bayesian false discovery probability was used to assess the noteworthiness of the meta-analysed array-specific interactions. RESULTS: Noteworthy evidence of interaction at ≤1% prior probability was observed for three single nucleotide polymorphism (SNP)-risk factor pairs. SNP rs4442975 was associated with a greater reduction of risk of ER-positive breast cancer [odds ratio (OR)int = 0.85 (0.78-0.93), Pint = 2.8 x 10-4] and overall breast cancer [ORint = 0.85 (0.78-0.92), Pint = 7.4 x 10-5) in current users of estrogen-progesterone therapy compared with non-users. This finding was supported by replication using OncoArray data of the previously reported interaction between rs13387042 (r2 = 0.93 with rs4442975) and current estrogen-progesterone therapy for overall disease (Pint = 0.004). The two other interactions suggested stronger associations between SNP rs6596100 and ER-negative breast cancer with increasing parity and younger age at first birth. CONCLUSIONS: Overall, our study does not suggest strong effect modification of common breast cancer susceptibility variants by established risk factors.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Alelos , Estudos de Casos e Controles , Europa (Continente) , Grupo com Ancestrais do Continente Europeu , Fator XIII , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/genética , Fatores de Risco
15.
J Natl Cancer Inst ; 112(2): 179-190, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31095341

RESUMO

BACKGROUND: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

16.
Cancer Epidemiol Biomarkers Prev ; 29(2): 477-486, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31826910

RESUMO

BACKGROUND: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. METHODS: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. RESULTS: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10-8; rs62558833, P = 7.5 × 10-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. CONCLUSIONS: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. IMPACT: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

17.
Int J Cancer ; 146(8): 2130-2138, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31265136

RESUMO

A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large-scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse-variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin-like growth factor receptor 1 and other membrane receptors (OR: 0.82-1.18, p values: 6.96 × 10-4 -3.28 × 10-8 ), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.


Assuntos
Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Locos de Características Quantitativas
18.
Int J Epidemiol ; 49(4): 1117-1131, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31872213

RESUMO

BACKGROUND: Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. METHODS: Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. RESULTS: Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08-1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. CONCLUSIONS: This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.

19.
PLoS Med ; 16(12): e1002998, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31860675

RESUMO

BACKGROUND: The United States Preventive Services Task Force supports individualised decision-making for prostate-specific antigen (PSA)-based screening in men aged 55-69. Knowing how the potential benefits and harms of screening vary by an individual's risk of developing prostate cancer could inform decision-making about screening at both an individual and population level. This modelling study examined the benefit-harm tradeoffs and the cost-effectiveness of a risk-tailored screening programme compared to age-based and no screening. METHODS AND FINDINGS: A life-table model, projecting age-specific prostate cancer incidence and mortality, was developed of a hypothetical cohort of 4.48 million men in England aged 55 to 69 years with follow-up to age 90. Risk thresholds were based on age and polygenic profile. We compared no screening, age-based screening (quadrennial PSA testing from 55 to 69), and risk-tailored screening (men aged 55 to 69 years with a 10-year absolute risk greater than a threshold receive quadrennial PSA testing from the age they reach the risk threshold). The analysis was undertaken from the health service perspective, including direct costs borne by the health system for risk assessment, screening, diagnosis, and treatment. We used probabilistic sensitivity analyses to account for parameter uncertainty and discounted future costs and benefits at 3.5% per year. Our analysis should be considered cautiously in light of limitations related to our model's cohort-based structure and the uncertainty of input parameters in mathematical models. Compared to no screening over 35 years follow-up, age-based screening prevented the most deaths from prostate cancer (39,272, 95% uncertainty interval [UI]: 16,792-59,685) at the expense of 94,831 (95% UI: 84,827-105,630) overdiagnosed cancers. Age-based screening was the least cost-effective strategy studied. The greatest number of quality-adjusted life-years (QALYs) was generated by risk-based screening at a 10-year absolute risk threshold of 4%. At this threshold, risk-based screening led to one-third fewer overdiagnosed cancers (64,384, 95% UI: 57,382-72,050) but averted 6.3% fewer (9,695, 95% UI: 2,853-15,851) deaths from prostate cancer by comparison with age-based screening. Relative to no screening, risk-based screening at a 4% 10-year absolute risk threshold was cost-effective in 48.4% and 57.4% of the simulations at willingness-to-pay thresholds of GBP£20,000 (US$26,000) and £30,000 ($39,386) per QALY, respectively. The cost-effectiveness of risk-tailored screening improved as the threshold rose. CONCLUSIONS: Based on the results of this modelling study, offering screening to men at higher risk could potentially reduce overdiagnosis and improve the benefit-harm tradeoff and the cost-effectiveness of a prostate cancer screening program. The optimal threshold will depend on societal judgements of the appropriate balance of benefits-harms and cost-effectiveness.


Assuntos
Detecção Precoce de Câncer , Antígeno Prostático Específico/análise , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Idoso , Análise Custo-Benefício , Detecção Precoce de Câncer/métodos , Inglaterra , Humanos , Incidência , Tábuas de Vida , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Medição de Risco
20.
Breast Cancer Res ; 21(1): 144, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847907

RESUMO

BACKGROUND: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. METHODS: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. RESULTS: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Área Sob a Curva , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Mutação em Linhagem Germinativa , Humanos , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/prevenção & controle , Países Baixos/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco
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