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1.
Cancer Res ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719099

RESUMO

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder associated with TP53 germline mutations and an increased lifetime risk of multiple primary cancers (MPC). Penetrance estimation of time to first and second primary cancer within LFS remains challenging due to limited data and the difficulty of characterizing the effects of a primary cancer on the penetrance of a second primary cancer. Using a recurrent events survival modeling approach that incorporates a family-wise likelihood to efficiently integrate the pedigree structure, we estimated the penetrance for both first and second primary cancer (PC) diagnosis from a pediatric sarcoma cohort at MD Anderson Cancer Center (MDACC, number of families=189; single primary cancer [SPC]=771; MPC=87). Validation of the risk prediction performance was performed using an independent MDACC clinical cohort of TP53 tested individuals (SPC=102; MPC=58). Findings showed that an individual diagnosed at a later age was more likely to be diagnosed with a second PC. Additionally, TP53 mutation carriers had a hazard ratio of 1.65 (95%CI: 1.1, 2.5) for developing a second PC versus SPC. The area under the ROC curve (AUC) for predicting individual outcomes of MPC versus SPC was 0.77. In summary, we provide the first set of penetrance estimates for SPC and MPC for TP53 germline mutation carriers, and demonstrate its accuracy for cancer risk assessment.

2.
Cancer Res ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719101

RESUMO

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome associated with an autosomal dominant mutation inheritance in the TP53 tumor suppressor gene and a wide spectrum of cancer diagnoses. The previously developed R package, LFSPRO, is capable of estimating the risk of an individual being a TP53 mutation carrier. However, an accurate estimation of the penetrance of different cancer types in LFS is crucial to improve the clinical characterization and management of high-risk individuals. Here, we developed a competing risk-based statistical model that incorporates the pedigree structure efficiently into the penetrance estimation and corrects for ascertainment bias while also increasing the effective sample size of this rare population. This enabled successful estimation of TP53 penetrance for three LFS cancer types: breast (BR), sarcoma (SA), and others (OT), from 186 pediatric sarcoma families collected at MD Anderson Cancer Center. Penetrance validation was performed on a combined dataset of two clinically ascertained family cohorts with cancer to overcome internal bias in each (total number of families=668). The age-dependent onset probability distributions of specific cancer types were different. For breast cancer, the TP53 penetrance went up at an earlier age than the reported BRCA1/2 penetrance. The prediction performance of the penetrance estimates was validated by the combined independent cohorts (BR=85, SA=540, OT=158). Areas under the ROC curves (AUCs) were 0.92 (BR), 0.75 (SA), and 0.81 (OT). The new penetrance estimates have been incorporated into the current LFSPRO R package in order to provide risk estimates for the diagnosis of breast cancer, sarcoma, or other cancers.

3.
Int J Cancer ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma, small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (PTWAS =1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (PTWAS =3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (PTWAS =6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influence lung cancer risk. This article is protected by copyright. All rights reserved.

4.
Neoplasia ; 21(11): 1102-1109, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31734631

RESUMO

Acquired uniparental disomy (aUPD) leads to homozygosity facilitating identification of monoallelically expressed genes. We analyzed single-nucleotide polymorphism array-based genotyping data of 448 head and neck squamous cell carcinoma (HNSCC) samples from The Cancer Genome Atlas to determine the frequency and distribution of aUPD regions and their association with survival, as well as to gain a better understanding of their influence on the tumor genome. We used expression data from the same dataset to identify differentially expressed genes between groups with and without aUPD. Univariate and multivariable Cox proportional hazards models were performed for survival analysis. We found that 82.14% of HNSCC samples carried aUPD; the most common regions were in chromosome 17p (31.25%), 9p (30.13%), and 9q (27.46%). In univariate analysis, five independent aUPD regions at chromosome 9p, two regions at chromosome 9q, and the CDKN2A region were associated with poor overall survival in all groups, including training and test sets and human papillomavirus (HPV)-negative samples. Forty-three genes in areas of aUPD including PD-L1 and CDKN2A were differentially expressed in samples with aUPD compared to samples without aUPD. In multivariable analysis, aUPD at the CDKN2A region was a significant predictor of overall survival in the whole cohort and in patients with HPV-negative HNSCC. aUPD at specific regions in the genome influences clinical outcomes of HNSCC and may be beneficial for selection of personalized therapy to prolong survival in patients with this disease.

5.
Carcinogenesis ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31630191

RESUMO

Genome-wide association study (GWAS)-identified single-nucleotide polymorphisms (SNPs) are tag SNPs located in both transcribed and noncoding regulatory DNA regions, rather than representing causal or functional variants for disease. To identify functional variants or genes for melanoma susceptibility, we used FUMA to perform functional annotation of the summary statistics of 2541 significant melanoma risk SNPs (P < 5×10-8) identified by GWAS. The original GWAS melanoma study included 15,990 cases and 26,409 controls, representing the largest international meta-analysis of melanoma susceptibility. We prioritized 330 unique genes, including those in immune cytokine signaling pathways, from 19 loci through positional, expression quantitative trait locus, and chromatin interaction mapping. In comparison, only 38 melanoma-related genes were identified in the original meta-analysis. In addition to the well-known melanoma susceptibility genes confirmed in the meta-analysis (MC1R, CDKN2A, TERT, OCA2, and ARNT/SETDB1), we also identified additional novel genes using FUMA to map SNPs to genes. Through chromatin interaction mapping, we prioritized IFNA7, IFNA10, IFNA16, IFNA17, IFNA14, IFNA6, IFNA21, IFNA4, IFNE, and IFNA5; these 10 most significant genes are all involved in immune system and cytokine signaling pathways. In the gene analysis, we identified 72 genes with a P < 2.5×10-6. The genes associated with melanoma risk were DEF8 (P = 1.09×10-57), DBNDD1 (P = 2.19×10-42), SPATA33 (P = 3.54×10-38), and MC1R (P = 1.04×10-36). In summary, this study identifies novel putative melanoma susceptibility genes and provides a guide for further experimental validation of functional variants and disease-related genes.

6.
Int J Cancer ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.

7.
Int J Epidemiol ; 48(5): 1493-1504, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31549173

RESUMO

BACKGROUND: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated. METHODS: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer. RESULTS: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk. CONCLUSIONS: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.

8.
Mol Carcinog ; 58(11): 2091-2103, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31435991

RESUMO

Glutamine dependence is a unique metabolic defect seen in cutaneous melanoma (CM), directly influencing the treatment and prognosis. Here, we investigated the associations between 6025 common single-nucleotide polymorphisms (SNPs) in 77 glutamine metabolic pathway genes with CM-specific survival (CMSS) using genotyping datasets from two published genome-wide association studies (GWASs). In the single-locus analysis, 76 SNPs were found to be significantly associated with CMSS (P < .050, false-positive report probability < 0.2 and Bayesian false discovery probability < 0.8) in the discovery dataset, of which seven SNPs were replicated in the validation dataset and three SNPs (HAL rs17676826T > C, LGSN rs12663017T > A, and NOXRED1 rs8012548A > G) independently predicted CMSS, with an effect-allele attributed adjusted hazards ratio of 1.52 (95% confidence interval = 1.19-1.93) and P < .001, 0.68 (0.54-0.87) and P = .002 and 0.62 (0.46-0.83) and P = .002, respectively. The model including the number of unfavorable genotypes (NUGs) of these three SNPs and covariates improved the five-year CMSS prediction (P = .012) than the one with other covariates only. Further expression quantitative trait loci (eQTL) analysis found that the LGSN rs12663017 A allele was significantly associated with increased messenger RNA (mRNA) expression levels (P = 8.89 × 10 -11 ) in lymphoblastoid cell lines of the 1000 Genomes Project database. In the analysis of the genotype tissue expression (GTEx) project datasets, HAL rs17676826 C and NOXRED1 rs8012548 G alleles were significantly associated with their mRNA expression levels in sun-exposed skin of the lower leg (P = 6.62 × 10-6 and 1.37 × 10-7 , respectively) and in sun-not-exposed suprapubic skin (P < .001 and 1.43 × 10-8 , respectively). Taken together, these genetic variants of glutamine-metabolic pathway genes may be promising predictors of survival in patients with CM.

9.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1228-1237, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31263055

RESUMO

BACKGROUND: Lung cancer remains the leading cause of cancer mortality with relatively few prognostic biomarkers. We investigated associations with overall survival for telomere length (TL) and genetic variation in chromosome 5p15.33, an established telomere maintenance locus. METHODS: Leukocyte TL was measured after diagnosis in 807 patients with non-small cell lung cancer (NSCLC) from the Princess Margaret Cancer Center in Toronto and assessed prospectively in 767 NSCLC cases from the Copenhagen City Heart Study and the Copenhagen General Population Study. Associations with all-cause mortality were tested for 723 variants in 5p15.33, genotyped in 4,672 NSCLC cases. RESULTS: Short telomeres (≤10th percentile) were associated with poor prognosis for adenocarcinoma in both populations: TL measured 6 months after diagnosis [HR = 1.65; 95% confidence intervals (CI), 1.04-2.64] and for those diagnosed within 5 years after blood sampling (HR = 2.42; 95% CI, 1.37-4.28). Short TL was associated with mortality in never smokers with NSCLC (HR = 10.29; 95% CI, 1.86-56.86) and adenocarcinoma (HR = 11.31; 95% CI, 1.96-65.24). Analyses in 5p15.33 identified statistically significant prognostic associations for rs56266421-G in LPCAT1 (HR = 1.86; 95% CI, 1.38-2.52; P = 4.5 × 10-5) in stage I-IIIA NSCLC, and for the SLC6A3 gene with OS in females with NSCLC (P = 1.6 × 10-3). CONCLUSIONS: Our findings support the potential clinical utility of TL, particularly for adenocarcinoma patients, while associations in chromosome 5p15.33 warrant further exploration. IMPACT: This is the largest lung cancer study of leukocyte TL and OS, and the first to examine the impact of the timing of TL measurement. Our findings suggest that extremely short telomeres are indicative of poor prognosis in NSCLC.

10.
Lancet Respir Med ; 7(10): 881-891, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326317

RESUMO

BACKGROUND: Genetic variation has an important role in the development of non-small-cell lung cancer (NSCLC). However, genetic factors for lung cancer have not been fully identified, especially in Chinese populations, which limits the use of existing polygenic risk scores (PRS) to identify subpopulations at high risk of lung cancer for prevention. We therefore aimed to identify novel loci associated with NSCLC risk, and generate a PRS and evaluate its utility and effectiveness in the prediction of lung cancer risk in Chinese populations. METHODS: To systematically identify genetic variants for NSCLC risk, we newly genotyped 19 546 samples from Chinese NSCLC cases and controls from the Nanjing Medical University Global Screening Array Project and did a meta-analysis of genome-wide association studies (GWASs) of 27 120 individuals with NSCLC and 27 355 without NSCLC (13 327 cases and 13 328 controls of Chinese descent as well as 13 793 cases and 14 027 controls of European descent). We then built a PRS for Chinese populations from all reported single-nucleotide polymorphisms that have been reported to be associated with lung cancer risk at genome-wide significance level. We evaluated the utility and effectiveness of the generated PRS in predicting subpopulations at high-risk of lung cancer in an independent prospective cohort of 95 408 individuals from the China Kadoorie Biobank (CKB) with more than 10 years' follow-up. FINDINGS: We identified 19 susceptibility loci to be significantly associated with NSCLC risk at p≤5·0 × 10-8, including six novel loci. When applied to the CKB cohort, the PRS of the risk loci successfully predicted lung cancer incident cases in a dose-response manner in participants at a high genetic risk (top 10%) than those at a low genetic risk (bottom 10%; adjusted hazard ratio 1·96, 95% CI 1·53-2·51; ptrend=2·02 × 10-9). Specially, we observed consistently separated curves of lung cancer events in individuals at low, intermediate, and high genetic risk, respectively, and PRS was an independent effective risk stratification indicator beyond age and smoking pack-years. INTERPRETATION: We have shown for the first time that GWAS-derived PRS can be effectively used in discriminating subpopulations at high risk of lung cancer, who might benefit from a practically feasible PRS-based lung cancer screening programme for precision prevention in Chinese populations. FUNDING: National Natural Science Foundation of China, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions, National Key R&D Program of China, Science Foundation for Distinguished Young Scholars of Jiangsu, and China's Thousand Talents Program.

11.
JAMA Netw Open ; 2(6): e195877, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31199453

RESUMO

Importance: It is unclear whether effective population-wide interventions that reduce risk factors and improve health result in sustained benefits to a community's health. If benefits do persist after a program is ended, interventions could be brief rather than maintained long term. Objective: To measure mortality and smoking rates in a rural community over decades before, during, and after prevention program reductions. Design, Setting, and Participants: This cross-sectional study compared smoking and mortality rates in a rural Maine county with other Maine counties over time by 5-year intervals. Multiple changes occurred between 2001 and 2015 in the physiological and behavioral risk factor reduction programs offered in the county. They included reductions in leadership, staff, institutional resources, data monitoring, and the programs themselves. Data were analyzed from May 2018 to March 2019. Intervention: Previous multifaceted interventions and outcome monitoring were withdrawn or diminished in the past decade. Main Outcomes and Measures: Smoking and age-adjusted mortality rates vs household income. Results: Reduced mortality rates in Franklin County in 1986 to 2005 reverted to those predicted by household incomes, relative to other Maine counties, by 2006 to 2015 (1986-1990 T score = -2.86 [P = .01] and 2001-2005 T score = -3.00 [P = .01] to 2006 to 2010 T score = -0.43 [P = .67] and 2011-2015 T score = -0.72 [P = .48]). Analysis of County Health Rankings data from 2010 to 2018 also showed that Franklin County's outcomes have reverted to no better than predicted by socioeconomic status. The county's T scores increased from -3.62 (P = .003) in 2010 to -0.41 (P = .69) in 2015 to 0.13 (P = .90) in 2018. Statewide association of income with mortality by analyses of variance showed that the R2 values have increased from the decades preceding 2000 (1976-1980, R2 = 0.21; P = .08; 1986-1990, R2 = 0.32; P = .02) to 2006 to 2010 (R2 = 0.73; P < .001) and 2011 to 2015 (R2 = 0.70; P < .001). Conclusions and Relevance: This study suggests that gains associated with population health interventions may be lost when the interventions are reduced. Adjusting outcome measures for socioeconomic status may allow quicker and more sensitive monitoring of intervention adequacy and success. The increasing trend of age-adjusted mortality in Maine and nationally to correlate inversely with incomes may warrant further community interventions, especially for poorer populations.

12.
Cancer Res ; 79(16): 4227-4241, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31239274

RESUMO

Approximately 20% of colorectal cancer patients with colorectal adenocarcinomas present with metastases at the time of diagnosis, and therapies that specially target these metastases are lacking. We present a novel approach for investigating transcriptomic differences between primary colorectal adenocarcinoma and distant metastases, which may help to identify primary tumors with high risk for future dissemination and to inform the development of metastasis-targeted therapies. To effectively compare the transcriptomes of primary colorectal adenocarcinoma and metastatic lesions at both the gene and pathway levels, we eliminated tissue specificity of the "host" organs where tumors are located and adjusted for confounders such as exposure to chemotherapy and radiation, and identified that metastases were characterized by reduced epithelial-mesenchymal transition (EMT) but increased MYC target and DNA-repair pathway activities. FBN2 and MMP3 were the most differentially expressed genes between primary tumors and metastases. The two subtypes of colorectal adenocarcinoma metastases that were identified, EMT inflammatory and proliferative, were distinct from the consensus molecular subtype (CMS) 3, suggesting subtype exclusivity. In summary, this study highlights transcriptomic differences between primary tumors and colorectal adenocarcinoma metastases and delineates pathways that are activated in metastases that could be targeted in colorectal adenocarcinoma patients with metastatic disease. SIGNIFICANCE: These findings identify a colorectal adenocarcinoma metastasis-specific gene-expression signature that is free from potentially confounding background signals coming from treatment exposure and the normal host tissue that the metastasis is now situated within.

13.
J Invest Dermatol ; 139(11): 2352-2358.e3, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31176707

RESUMO

To investigate the role of tumor cytokines/chemokines in melanoma immune response, we estimated the proportions of immune cell subsets in melanoma tumors from The Cancer Genome Atlas, followed by evaluation of the association between cytokine/chemokine expression and these subsets. We then investigated the association of immune cell subsets, chemokines, and cytokines with patient survival. Finally, we evaluated the immune cell tumor-infiltrating lymphocyte (TIL) score for correlation with melanoma patient outcome in a separate cohort. There was good agreement between RNA sequencing estimation of T-cell subset and pathologist-determined TIL score. Expression levels of cytokines IL-12A, IFNG, and IL-10, and chemokines CXCL9 and CXCL10 were positively correlated with PDCD1, CTLA-4, and CD8+ T-cell subset, but negatively correlated with tumor purity (Bonferroni-corrected P < 0.05). In multivariable analysis, higher expression levels of cytokines IFN-γ and TGFB1, but not chemokines, were associated with improved overall survival. A higher expression level of CD8+ T-cell subset was also associated with improved overall survival (hazard ratio [HR] = 0.06, 95% confidence interval [CI] = 0.01-0.35, P = 0.002). Finally, multivariable analysis showed that patients with a brisk TIL score had improved melanoma-specific survival than those with a nonbrisk score (HR = 0.51, 95% CI = 0.27-0.98, P = 0.0423). These results suggest that the expression of specific tumor cytokines represents important biomarkers of melanoma immune response.

14.
J Community Genet ; 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31016603

RESUMO

Lynch syndrome (LS), a hereditary cancer syndrome, accounts for approximately 3% of colorectal cancers (CRC). Positive health behaviors and surveillance are preventive strategies, but research on whether recommended behavioral guidelines are followed by individuals with LS is limited. Additional health education and promotion could be beneficial to the improved survivorship of CRC survivors. Explore health and lifestyle behaviors in CRC survivors with and without LS. We conducted a case-control study of CRC survivors with and without LS using a mailed questionnaire. Recruitment was conducted via patient registries at The University of Texas MD Anderson Cancer Center (cases n = 33; controls n = 75) and through social media (cases n = 42). CRC survivors with and without LS in our study had substantially lower smoking prevalence (5.5% and 2.7%) compared to national prevalence (18.0%). However, they had higher levels of alcohol consumption (36.8% and 10.3% for male and female LS survivors, respectively, and 35.8% and 22.0% for male and female sporadic survivors, respectively) compared to national prevalence of 13.88% for males and 6.02% for females. Both groups of CRC survivors participate in negative health behaviors that impact survivorship. More research is needed to examine the relationship between personal engagement in preventive behaviors and patient-provider relationships to improve health behaviors and explore strategies for intervention. Additionally, better health education and lifestyle change recommendations would promote and reinforce positive health outcomes in the CRC population and especially in LS survivors.

15.
Int J Cancer ; 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30963577

RESUMO

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have <80% EA, or self-identify as non-White. We estimated global and local ancestry using fastStructure and RFMix, respectively, using 1,000 genomes project reference populations. Within groups with ≥40% AA (AFR≥0.4 ), and ≥15% NAA (AMR≥0.15 ), genome-wide association between local EA and glioma was evaluated using logistic regression conditioned on global EA for all gliomas. We identified two regions (7q21.11, p = 6.36 × 10-4 ; 11p11.12, p = 7.0 × 10-4 ) associated with increased EA, and one associated with decreased EA (20p12.13, p = 0.0026) in AFR≥0.4 . In addition, we identified a peak at rs1620291 (p = 4.36 × 10-6 ) in 7q21.3. Among AMR≥0.15 , we found an association between increased EA in one region (12q24.21, p = 8.38 × 10-4 ), and decreased EA in two regions (8q24.21, p = 0. 0010; 20q13.33, p = 6.36 × 10-4 ). No other significant associations were identified. This analysis identified an association between glioma and two regions previously identified in EA populations (8q24.21, 20q13.33) and four novel regions (7q21.11, 11p11.12, 12q24.21 and 20p12.13). The identifications of novel association with EA suggest regions to target for future genetic association studies.

16.
Cancer Epidemiol Biomarkers Prev ; 28(4): 715-723, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30894353

RESUMO

BACKGROUND: Identifying genetic variants with pleiotropic associations across multiple cancers can reveal shared biologic pathways. Prior pleiotropic studies have primarily focused on European-descent individuals. Yet population-specific genetic variation can occur, and potential pleiotropic associations among diverse racial/ethnic populations could be missed. We examined cross-cancer pleiotropic associations with lung cancer risk in African Americans. METHODS: We conducted a pleiotropic analysis among 1,410 African American lung cancer cases and 2,843 controls. We examined 36,958 variants previously associated (or in linkage disequilibrium) with cancer in prior genome-wide association studies. Logistic regression analyses were conducted, adjusting for age, sex, global ancestry, study site, and smoking status. RESULTS: We identified three novel genomic regions significantly associated (FDR-corrected P <0.10) with lung cancer risk (rs336958 on 5q14.3, rs7186207 on 16q22.2, and rs11658063 on 17q12). On chromosome16q22.2, rs7186207 was significantly associated with reduced risk [OR = 0.43; 95% confidence interval (CI), 0.73-0.89], and functional annotation using GTEx showed rs7186207 modifies DHODH gene expression. The minor allele at rs336958 on 5q14.3 was associated with increased lung cancer risk (OR = 1.47; 95% CI, 1.22-1.78), whereas the minor allele at rs11658063 on 17q12 was associated with reduced risk (OR = 0.80; 95% CI, 0.72-0.90). CONCLUSIONS: We identified novel associations on chromosomes 5q14.3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers. This is the first study to examine cross-cancer pleiotropic associations for lung cancer in African Americans. IMPACT: Our findings demonstrate novel cross-cancer pleiotropic associations with lung cancer risk in African Americans.

17.
Gynecol Oncol ; 153(2): 343-355, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898391

RESUMO

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.


Assuntos
Carcinoma Epitelial do Ovário/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
18.
Int J Cancer ; 145(10): 2619-2628, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30734280

RESUMO

Fatty acids play a key role in cellular bioenergetics, membrane biosynthesis and intracellular signaling processes and thus may be involved in cancer development and progression. In the present study, we comprehensively assessed associations of 14,522 common single-nucleotide polymorphisms (SNPs) in 149 genes of the fatty-acid synthesis pathway with cutaneous melanoma disease-specific survival (CMSS). The dataset of 858 cutaneous melanoma (CM) patients from a published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used as the discovery dataset, and the identified significant SNPs were validated by a dataset of 409 CM patients from another GWAS from the Nurses' Health and Health Professionals Follow-up Studies. We found 40 noteworthy SNPs to be associated with CMSS in both discovery and validation datasets after multiple comparison correction by the false positive report probability method, because more than 85% of the SNPs were imputed. By performing functional prediction, linkage disequilibrium analysis, and stepwise Cox regression selection, we identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted CMSS, with an allelic hazards ratio of 0.66 (95% confidence interval = 0.51-0.84 and p = 8.34 × 10-4 ) and 2.29 (1.55-3.39 and p = 3.61 × 10-5 ), respectively. Finally, the ELOVL2 rs3734398 variant CC genotype was found to be associated with a significantly increased mRNA expression level. These SNPs may be potential markers for CM prognosis, if validated by additional larger and mechanistic studies.

19.
Cancer Genet ; 231-232: 67-79, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30803560

RESUMO

BACKGROUND: Usually, genes with a higher-than-expected number of somatic mutations in tumor samples are assumed to be cancer related. We identified genes with a fewer-than-expected number of somatic mutations - "untouchable genes". METHODS: To predict the expected number of somatic mutations, we used a linear regression model with the number of mutations in the gene as an outcome, and gene characteristics, including gene size, nucleotide composition, level of evolutionary conservation, expression level and others, as predictors. Analysis of residuals from the regression model was used to compare the observed and predicted number of mutations. RESULTS: We have identified 19 genes with a less-than-expected number of loss-off-function (nonsense, frameshift or pathogenic missense) mutations - i.e., untouchable genes. The number of silent or neutral missense mutations in untouchable genes was equal or higher than the expected number. Many mucins, including MUC16, MUC17, MUC6, MUC5AC, MUC5B, and MUC12, are untouchable. We hypothesized that untouchable mucins help tumor cells to avoid immune response by providing a protective coat that prevents direct contact between effector immune cells, e.g., cytotoxic T-cells, and tumor cells. Survival analysis of available TCGA data demonstrated that overall survival of patients with low (below the median) expression of untouchable mucins was better compared to patients with high expression of untouchable mucins. Aside from mucins, we have identified a number of other untouchable genes. CONCLUSIONS: Untouchable genes may be ideal targets for cancer treatment since suppression of untouchable genes is expected to inhibit survival of tumor cells.


Assuntos
Genes Neoplásicos , Genoma Humano , Neoplasias/genética , Neoplasias/terapia , Códon sem Sentido/genética , Mutação da Fase de Leitura/genética , Humanos , Modelos Lineares , Mutação com Perda de Função/genética , Mucinas/genética , Mutação de Sentido Incorreto/genética , Análise de Sobrevida
20.
Neoplasia ; 21(2): 197-205, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30616092

RESUMO

Smoking and alcohol intake are major risk factors in head and neck squamous cell carcinomas (HNSCCs). Although the link between TP53 mutation and smoking has been well established, very little is known about the link between acquired uniparental disomy (aUPD) and smoking and/or alcohol consumption or other clinical characteristics. We used TCGA genomic data to investigate whether smoking, alcohol intake, clinical and demographic variables, HPV status and TP53 mutation are associated with aUPD at specific chromosomal regions. In multivariate analysis, we found association between aUPD regions and risk factors and clinical variables of disease. aUPD regions on chromosome 4q, 5q, 9p, 9q, 13q, 17p and CDKN2A occurred significantly more often in patients with TP53-mutated HNSCC than in those with wild-type HNSCC, while aUPD regions on chromosome 9p and at CDKN2A were significantly more frequent in females than in males. Besides, aUPD occurred more frequent in HPV-positive than in HPV-negative samples with all HNSCC and larynx cancers on chromosome 9q 15q and 17p. Moreover, aUPD on CDKN2A region occurred more often in alcohol drinkers than nondrinkers in patients with all HNSCC and oral cavity cancers, while aUPD region on chromosome 5q occurred less in alcohol drinkers than nondrinkers in patients with all HNSCC and oral cavity cancers. Similarly, aUPD region on chromosome 5q occurred less in smokers than nonsmokers in patients with all HNSCC and oral cavity cancers. In conclusion, aUPD regions are not random, and certain regions are associated with risk factors for disease, and with TP53 mutation status.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Alelos , Infecções por Papillomavirus/complicações , Fumar/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Proteína Supressora de Tumor p53/genética , Dissomia Uniparental/genética , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Humanos , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico
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