Publications by authors named "Xifeng Wu"

507 Publications

Identification of 22 susceptibility loci associated with testicular germ cell tumors.

Nat Commun 2021 07 23;12(1):4487. Epub 2021 Jul 23.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95 percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
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http://dx.doi.org/10.1038/s41467-021-24334-yDOI Listing
July 2021

Genetic determinants of multiple myeloma risk within the Wnt/beta-catenin signaling pathway.

Cancer Epidemiol 2021 Aug 30;73:101972. Epub 2021 Jun 30.

Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States. Electronic address:

Background: Aberrant Wnt/beta-catenin pathway activation is implicated in Multiple Myeloma (MM) development, but little is known if genetic variants within this pathway contribute to MM susceptibility.

Methods: We performed a discovery candidate pathway analysis in 269 non-Hispanic white MM cases and 272 controls focusing on 171 variants selected from 26 core genes within the Wnt/beta-catenin pathway. Significant candidate variants (P < 0.05) were selected for validation in internal and external non-Hispanic white populations totaling 818 cases and 1209 controls. We also examined significant variants in non-Hispanic black and Hispanic case/control study populations to identify potential differences by race/ethnicity. Possible biological functions of candidate variants were predicted in silico.

Results: Seven variants were significantly associated with MM risk in non-Hispanic whites in the discovery population, of which LRP6:rs7966410 (OR: 0.57; 95 % CI: 0.38-0.88; P = 9.90 × 10) and LRP6:rs7956971 (OR: 0.64; 95 % CI: 0.44-0.95; P = 0.027) remained significant in the internal and external populations. CSNK1D:rs9901910 replicated among all three racial/ethnic groups, with 2-6 fold increased risk of MM (OR: 2.40; 95 % CI: 1.67-3.45; P = 2.43 × 10 - non-Hispanic white; OR: 6.42; 95 % CI: 2.47-16.7; P = 3.14 × 10 - non-Hispanic black; OR: 4.31; 95 % CI: 1.83-10.1; P = 8.10 × 10 - Hispanic). BTRC:rs7916830 was associated with a significant 37 % and 24 % reduced risk of MM in the non-Hispanic white (95 % CI: 0.49-0.82; P = 5.60 × 10) and non-Hispanic Black (95 % CI: 0.60-0.97; P = 0.028) population, respectively. In silico tools predicted that these loci altered function through via gene regulation.

Conclusion: We identified several variants within the Wnt/beta-catenin pathway associated with MM susceptibility. Findings of this study highlight the potential genetic role of Wnt/beta-catenin signaling in MM etiology among a diverse patient population.
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http://dx.doi.org/10.1016/j.canep.2021.101972DOI Listing
August 2021

Predicting COVID-19 epidemiological trend by applying population mobility data in two-stage modeling.

Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 02;50(1):68-73

Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases,Zhejiang University,Hangzhou 310003,China.

:To predict the epidemiological trend of coronavirus disease 2019 (COVID-19) by mathematical modeling based on the population mobility and the epidemic prevention and control measures. : As of February 8,2020,the information of 151 confirmed cases in Yueqing,Zhejiang province were obtained,including patients' infection process,population mobility between Yueqing and Wuhan,etc. To simulate and predict the development trend of COVID-19 in Yueqing, the study established two-stage mathematical models,integrating the population mobility data with the date of symptom appearance of confirmed cases and the transmission dynamics of imported and local cases. : It was found that in the early stage of the pandemic,the number of daily imported cases from Wuhan (using the date of symptom appearance) was positively associated with the number of population travelling from Wuhan to Yueqing on the same day and 6 and 9 days before that. The study predicted that the final outbreak size in Yueqing would be 170 according to the number of imported cases estimated by consulting the population number travelling from Wuhan to Yueqing and the susceptible-exposed-infectious-recovered (SEIR) model; while the number would be 165 if using the reported daily number of imported cases. These estimates were close to the 170,the actual monitoring number of cases in Yueqing as of April 27,2020. : The two-stage modeling approach used in this study can accurately predict COVID-19 epidemiological trend.
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http://dx.doi.org/10.3724/zdxbyxb-2021-0043DOI Listing
February 2021

Impact of socioeconomic status,population mobility and control measures on COVID-10 development in major cities of China.

Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 02;50(1):52-60

Yale School of Public Health,Yale University,New Haven 06520,Connecticut,USA.

:To evaluate the impact of socioeconomic status,population mobility,prevention and control measures on the early-stage coronavirus disease 2019 (COVID-19) development in major cities of China. : The rate of daily new confirmed COVID-19 cases in the 51 cities with the largest number of cumulative confirmed cases as of February 19,2020 (except those in Hubei province) were collected and analyzed using the time series cluster analysis. It was then assessed according to three aspects,that is, socioeconomic status,population mobility,and control measures for the pandemic. : According to the analysis on the 51 cities,4 development patterns of COVID-19 were obtained,including a high-incidence pattern (in Xinyu),a late high-incidence pattern (in Ganzi),a moderate incidence pattern (in Wenzhou and other 12 cities),and a low and stable incidence pattern (in Hangzhou and other 35 cities). Cities with different types and within the same type both had different scores on the three aspects. : There were relatively large difference on the COVID-19 development among different cities in China,possibly affected by socioeconomic status,population mobility and prevention and control measures that were taken. Therefore,a timely public health emergency response and travel restriction measures inside the city can interfere the development of the pandemic. Population flow from high risk area can largely affect the number of cumulative confirmed cases.
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http://dx.doi.org/10.3724/zdxbyxb-2021-0028DOI Listing
February 2021

Impact of Wuhan lockdown on the spread of COVID-19 in China: a study based on the data of population mobility.

Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 02;50(1):61-67

Department of Surgical Oncology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310016,China.

This study aimed to quantitatively assess the effectiveness of the Wuhan lockdown measure on controlling the spread of coronavirus diesase 2019 (COVID-19). : Firstly,estimate the daily new infection rate in Wuhan before January 23,2020 when the city went into lockdown by consulting the data of Wuhan population mobility and the number of cases imported from Wuhan in 217 cities of Mainland China. Then estimate what the daily new infection rate would have been in Wuhan from January 24 to January 30th if the lockdown measure had been delayed for 7 days,assuming that the daily new infection in Wuhan after January 23 increased in a high,moderate and low trend respectively (using exponential, linear and logarithm growth models). Based on that,calculate the number of infection cases imported from Wuhan during this period. Finally,predict the possible impact of 7-day delayed lockdown in Wuhan on the epidemic situation in China using the susceptible-exposed-infectious-removed (SEIR) model. : The daily new infection rate in Wuhan was estimated to be 0.021%,0.026%,0.029%,0.033% and 0.070% respectively from January 19 to January 23. And there were at least 20 066 infection cases in Wuhan by January 23,2020. If Wuhan lockdown measure had been delayed for 7 days,the daily new infection rate on January 30 would have been 0.335% in the exponential growth model,0.129% in the linear growth model,and 0.070% in the logarithm growth model. Correspondingly,there would have been 32 075,24 819 and 20 334 infection cases travelling from Wuhan to other areas of Mainland China,and the number of cumulative confirmed cases as of March 19 in Mainland China would have been 3.3-3.9 times of the officially reported number. Conclusions: Timely taking city-level lockdown measure in Wuhan in the early stage of COVID-19 outbreak is essential in containing the spread of the disease in China.
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http://dx.doi.org/10.3724/zdxbyxb-2021-0021DOI Listing
February 2021

Human ribonuclease 1 serves as a secretory ligand of ephrin A4 receptor and induces breast tumor initiation.

Nat Commun 2021 05 13;12(1):2788. Epub 2021 May 13.

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Human ribonuclease 1 (hRNase 1) is critical to extracellular RNA clearance and innate immunity to achieve homeostasis and host defense; however, whether it plays a role in cancer remains elusive. Here, we demonstrate that hRNase 1, independently of its ribonucleolytic activity, enriches the stem-like cell population and enhances the tumor-initiating ability of breast cancer cells. Specifically, secretory hRNase 1 binds to and activates the tyrosine kinase receptor ephrin A4 (EphA4) signaling to promote breast tumor initiation in an autocrine/paracrine manner, which is distinct from the classical EphA4-ephrin juxtacrine signaling through contact-dependent cell-cell communication. In addition, analysis of human breast tumor tissue microarrays reveals a positive correlation between hRNase 1, EphA4 activation, and stem cell marker CD133. Notably, high hRNase 1 level in plasma samples is positively associated with EphA4 activation in tumor tissues from breast cancer patients, highlighting the pathological relevance of the hRNase 1-EphA4 axis in breast cancer. The discovery of hRNase 1 as a secretory ligand of EphA4 that enhances breast cancer stemness suggests a potential treatment strategy by inactivating the hRNase 1-EphA4 axis.
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http://dx.doi.org/10.1038/s41467-021-23075-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119676PMC
May 2021

Smoking and nasopharyngeal cancer: individual data meta-analysis of six prospective studies on 334 935 men.

Int J Epidemiol 2021 07;50(3):975-986

School of Public Health, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong.

Background: The role of smoking in nasopharyngeal carcinoma (NPC) remains uncertain, especially in endemic regions. We conducted an individual participant data (IPD) meta-analysis of prospective cohort studies to investigate the associations between smoking exposure and risk of NPC.

Methods: We obtained individual participant data of 334 935 male participants from six eligible population-based cohorts in NPC-endemic regions, including two each in Guangzhou and Taiwan, and one each in Hong Kong and Singapore. We used one- and two-stage approaches IPD meta-analysis and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of NPC for smoking exposure adjusting for age and drinking status.

Results: During 2 961 315 person-years of follow-up, 399 NPC evens were ascertained. Risks of NPC were higher in ever versus never smokers (HRone-stage = 1.32, 95% CI = 1.07-1.63, P = 0.0088; HRtwo-stage = 1.27, 1.01-1.60, 0.04). These positive associations appeared to be stronger in ever smokers who consumed 16+ cigarettes/day (HRone-stage = 1.67, 95% CI = 1.29-2.16, P = 0.0001), and in those who started smoking at age younger than 16 (2.16, 1.33-3.50, 0.0103), with dose-response relationships (P-values for trend = 0.0028 and 0.0103, respectively). Quitting (versus daily smoking) showed a small reduced risk (stopped for 5+ years: HRone-stage = 0.91, 95% CI = 0.60-1.39, P = 0.66; for former smokers: HRtwo-stage = 0.84, 0.61-1.14, 0.26).

Conclusions: This first IPD meta-analysis from six prospective cohorts in endemic regions has provided robust observational evidence that smoking increased NPC risk in men. NPC should be added to the 12-16 cancer sites known to be tobacco-related cancers. Strong tobacco control policies, preventing young individuals from smoking, would reduce NPC risk in endemic regions.
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http://dx.doi.org/10.1093/ije/dyab060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271191PMC
July 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021

HIF3A DNA methylation, obesity and weight gain, and breast cancer risk among Mexican American women.

Obes Res Clin Pract 2020 Nov - Dec;14(6):548-553. Epub 2020 Oct 26.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Family Medicine and Population Health, School of Medicine, Virginia Commonwealth University, VA, USA. Electronic address:

Objective: In previous epigenome-wide association studies, Hypoxia inducible Factor 3 Alpha Subunit (HIF3A) DNA methylation has been reported to be associated with body mass index (BMI) and weight change. However, none of these studies have included Mexican Americans.

Methods: In the current study, we assessed levels of HIF3A methylation in 927 Mexican American women identified from Mano-A-Mano, the Mexican American Cohort study.

Results: Significantly higher methylation levels at three CpG sites (position 46801557, 46801642, and 46801699) were observed in obese women compared to non-obese women (P < 0.05). Furthermore, we found that elevated methylation levels at those three CpG sites were associated with significant weight gain (P < 0.05), defined as an increase in BMI by at least one category between the baseline and the follow-up, with a median follow-up time of 39 months. Then, using pre-diagnostic blood DNA samples, we found increased DNA methylation at CpG 46801642 to be associated with a 1.35-fold increased risk of breast cancer (Hazard Ratio (HR) = 1.35, 95% Confidence Interval (CI): 1.02, 3.01), with a median follow-up time of 127 months. Using the Cancer Genome Atlas (TCGA) data, we further found that levels of HIF3A were significantly higher-methylated and down-regulated in breast tumor than in normal tissues (P < 1 × 10 for both).

Conclusion: Thus, our results provide evidence to support the role of HIF3A in obesity, weight gain, and the development of breast cancer.
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http://dx.doi.org/10.1016/j.orcp.2020.10.001DOI Listing
October 2020

Different transmission dynamics of COVID-19 and influenza suggest the relative efficiency of isolation/quarantine and social distancing against COVID-19 in China.

Clin Infect Dis 2020 Oct 20. Epub 2020 Oct 20.

School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, P.R. China.

Background: Non-pharmaceutical interventions (NPIs) against Coronavirus Disease 2019 (COVID-19) are vital to reducing the transmission risks. However, the relative efficiency of social distancing against COVID-19 remains controversial, since social distancing and isolation/quarantine were implemented almost at the same time in China.

Methods: In this study, surveillance data of COVID-19 and seasonal influenza in the year 2018-2020 were used to quantify the relative efficiency of NPIs against COVID-19 in China, since isolation/quarantine was not used for the influenza epidemics. Given that the relative age-dependent susceptibility to influenza and COVID-19 may vary, an age-structured Susceptible-Infected-Recovered model was built to explore the efficiency of social distancing against COVID-19 under different population susceptibility scenarios.

Results: The mean effective reproductive number, Rt, of COVID-19 before NPIs was 2.12 (95% confidential interval (CI): 2.02-2.21). By March 11, 2020, the overall reduction in Rt of COVID-19 was 66.1% (95% CI: 60.1%-71.2%). In the epidemiological year 2019/20, influenza transmissibility reduced by 34.6% (95% CI: 31.3%-38.2%) compared with that in the epidemiological year 2018/19. Under the observed contact patterns changes in China, social distancing had similar efficiency against COVID-19 in three different scenarios. By assuming same efficiency of social distancing against seasonal influenza and COVID-19 transmission, isolation/quarantine and social distancing could lead to a 48.1% (95% CI: 35.4%-58.1%) and 34.6% (95% CI: 31.3%-38.2%) reduction of the transmissibility of COVID-19.

Conclusions: Though isolation/quarantine is more effective than social distancing, given that typical basic reproductive number of COVID-19 is 2-3, isolation/quarantine alone could not contain the COVID-19 pandemic effectively in China.
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http://dx.doi.org/10.1093/cid/ciaa1584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665384PMC
October 2020

Long noncoding RNA LINC00467 facilitates the progression of acute myeloid leukemia by targeting the miR-339/SKI pathway.

Leuk Lymphoma 2021 02 15;62(2):428-437. Epub 2020 Oct 15.

Department of Hematology, Jinan People's Hospital Affiliated to Shandong First Medical University, Jinan City People's Hospital, Jinan, China.

A growing body of evidence indicates that long non-coding RNA (lncRNA) is involved in the development and progression of many diseases. It has been reported that lncRNA LINC00467 is disregulated in multiple tumors, while its role in acute myeloid leukemia (AML) is still unknown. Here, we find that LINC00467 expression is significantly increased in AML specimens and cell lines. Further investigations show that knockdown of LINC00467 inhibits the malignant phenotypes of AML cells. Consistently, LINC00467 knockdown slows AML progression in immunodeficient mice. Interestingly, microRNA-339 (miR-339) is upregulated and its target gene SKI, an oncogene, is downregulated in AML cells after LINC00467 knockdown. More importantly, inhibition of miR-339 can largely abolish the effect of LINC00467 knockdown on AML cells. Collectively, our data demonstrate that LINC00467 plays an important role in the pathogenesis of AML by targeting the miR-339/SKI pathway, which provides a new sight for the subsequent treatment of AML.
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http://dx.doi.org/10.1080/10428194.2020.1832667DOI Listing
February 2021

Circulating adipokine concentrations and risk of five obesity-related cancers: A Mendelian randomization study.

Int J Cancer 2021 04 26;148(7):1625-1636. Epub 2020 Oct 26.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.
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http://dx.doi.org/10.1002/ijc.33338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894468PMC
April 2021

Validation of plasma metabolites associated with breast cancer risk among Mexican Americans.

Cancer Epidemiol 2020 12 30;69:101826. Epub 2020 Sep 30.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States.

In our previous breast cancer case control study in Hispanics, we found 14 metabolites whose levels differed between cases and controls. To validate the results, we carried out a nested case control study of 100 incident breast cancer and 100 matched healthy women identified from the Mano-A-Mano Mexican American Cohort study. With the adjustment of parity, education, birth place, language acculturation, BMI category, smoking, drinking, physical activity, and sitting time, 4 metabolites were associated with breast cancer risk: 3-hydroxyoctanoate (Odds ratio (OR) = 1.51, 95% confidence interval (CI): 1.10, 3.47), 3-hydroxybutyrate (BHBA) (OR = 1.42, 95%CI: 1.01, 3.72), linoleate (18:2n6) (OR = 1.39, 95% CI: 1.07, 4.04), and bilirubin (OR = 0.54, 95%CI: 0.42, 0.95). Then, we used 3 non-redundant metabolites, namely 3-hydroxyoctanoate, linoleate (18:2n6), and bilirubin, to generate a metabolic risk score. Increased metabolites risk score was associated with a 1.67-fold increased risk of breast cancer (OR = 1.67, 95%CI: 1.32, 3.94). And the significant association was more evident among those who were diagnosed with cancer earlier during the follow-up (≤ 5 years) than their counterparts. In conclusion, we identified four significant metabolites which may help elucidate metabolic pathways that contribute to breast carcinogenesis. Our findings warrant further replication efforts.
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http://dx.doi.org/10.1016/j.canep.2020.101826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710579PMC
December 2020

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genet Epidemiol 2021 Feb 14;45(1):99-114. Epub 2020 Sep 14.

Faculty of Medical Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.
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http://dx.doi.org/10.1002/gepi.22358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855632PMC
February 2021

Immune checkpoint-related serum proteins and genetic variants predict outcomes of localized prostate cancer, a cohort study.

Cancer Immunol Immunother 2021 Mar 9;70(3):701-712. Epub 2020 Sep 9.

Center for Clinical Big Data and Analytics, Bioinformatics and Big Data, The Second Affiliated Hospital and School of Public Health, Zhejiang University School of Medicine, 866 Yuhangtang Rd, Hangzhou, 310058, PR China.

Background: The clinical predictors and biological mechanisms for localized prostate cancer (PCa) outcomes remain mostly unknown. We aim to evaluate the role of serum immune-checkpoint-related (ICK) proteins and genetic variations in predicting outcomes of localized PCa.

Methods: We profiled the serum levels of 14 ICK-related proteins (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, Tim-3, CD28, CD80, 4-1BB, CD27, and CTLA-4) in 190 patients with localized PCa. The genotypes of 97 single nucleotide polymorphisms (SNPs) from 19 ICK-related genes were analyzed in an extended population (N = 1762). Meta-data from ArrayExpress and TCGA was employed to validate and to probe functional data. Patients were enrolled and tumor aggressiveness, biochemical recurrence (BCR), and progression information were obtained. Statistical analyses were performed analyzing associations between serum biomarkers, genotypes, mRNA and outcomes.

Results: We showed that serum (s)BTLA and sTIM3 levels were associated with PCa aggressiveness (P < 0.05). sCD28, sCD80, sCTLA4, sGITR, sHVEM and sIDO correlated with both BCR and progression risks (all P < 0.05). We further identified ICK variants were significantly associated with aggressiveness, BCR and progression. Among them, 4 SNPs located in CD80 (rs7628626, rs12695388, rs491407, rs6804441) were not only associated with BCR and progression risk, but also correlated with sCD80 level (P < 0.01). rs491407 was further validated in an independent cohort. The CD80 mRNA expression was associated with BCR (HR, 1.85, 95% CI 1.06-3.22, P = 0.03) in meta-analysis of validation cohorts.

Conclusion: We highlight the prognostic value of serum ICK-related proteins for predicting aggressiveness, BCR and progression of PCa. The genetic variations and mRNA expression in CD80 could be predictors and potential targets of localized PCa.
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http://dx.doi.org/10.1007/s00262-020-02718-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907032PMC
March 2021

Household transmission of COVID-19-a systematic review and meta-analysis.

J Infect 2020 12 25;81(6):979-997. Epub 2020 Aug 25.

School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446647PMC
December 2020

Genetic associations of T cell cancer immune response-related genes with T cell phenotypes and clinical outcomes of early-stage lung cancer.

J Immunother Cancer 2020 08;8(2)

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States

Background: Recent advances in T cell-related immunotherapy have brought remarkable progress in the treatment of non-small cell lung cancer (NSCLC). However, whether and how genetic variations of T cell cancer immune response genes can influence clinical outcomes of NSCLC patients remain obscure.

Methods: In this multiphase study, we assessed 2450 single-nucleotide polymorphisms (SNPs) from 280 T cell cancer immune response-related genes in 941 early-stage NSCLC patients (discovery n=536; validation n=405) to analyze the variants' associations with outcomes and to observe the effects on T cell phenotypes.

Results: We found 14 SNPs in 10 genes were associated with NSCLC outcomes (p<0.05) in both phases. Among them, :rs1964986 was the most significant variant associated with recurrence risk after meta-analysis (HR 1.84, 95% CI 1.35 to 2.52, p=1.15E-04), while :rs10108662 was the most significant SNP associated with death risk (HR 1.87, 95% CI 1.40 to 2.51, p=2.17E-05). Analysis of unfavorable genotypes indicated cumulative effects on death and recurrence risks. Seven treatment-specific variants were found to predict opposite outcomes in surgery-only and surgery-plus-chemotherapy subgroups. Expression quantitative trait loci analysis indicated that six SNPs significantly correlated with their corresponding gene expression. T cells from high-risk subjects displayed reduced degranulation (p=0.02) and decreased cytotoxicity against cancer cells (p<0.01). Gene expression profile indicated increased IDO1 expression and decreased IL2, PRF and GZMB expression in high-risk subjects.

Conclusions: Genetic variations in T cell cancer immune response pathways can impact outcomes and may be served as predictors for treatment efficacy in early-stage NSCLC patients. The correlation between immune genotypes and T cell antitumor immunity suggests a biological link between host immune genetics and NSCLC prognosis.
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http://dx.doi.org/10.1136/jitc-2019-000336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412613PMC
August 2020

Pathway Analysis of Renal Cell Carcinoma Genome-Wide Association Studies Identifies Novel Associations.

Cancer Epidemiol Biomarkers Prev 2020 10 30;29(10):2065-2069. Epub 2020 Jul 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Background: Much of the heritable risk of renal cell carcinoma (RCC) associated with common genetic variation is unexplained. New analytic approaches have been developed to increase the discovery of risk variants in genome-wide association studies (GWAS), including multi-locus testing through pathway analysis.

Methods: We conducted a pathway analysis using GWAS summary data from six previous scans (10,784 cases and 20,406 controls) and evaluated 3,678 pathways and gene sets drawn from the Molecular Signatures Database. To replicate findings, we analyzed GWAS summary data from the UK Biobank (903 cases and 451,361 controls) and the Genetic Epidemiology Research on Adult Health and Aging cohort (317 cases and 50,511 controls).

Results: We identified 14 pathways/gene sets associated with RCC in both the discovery ( < 1.36 × 10, the Bonferroni correction threshold) and replication ( < 0.05) sets, 10 of which include components of the PI3K/AKT pathway. In tests across 2,035 genes in these pathways, associations (Bonferroni corrected < 2.46 × 10 in discovery and replication sets combined) were observed for , and . The strongest SNP signal was for rs12124078 ( = 2.6 × 10; = 1.5 × 10; = 6.9 × 10), a expression quantitative trait locus.

Conclusions: Our pathway analysis implicates genetic variation within the PI3K/AKT pathway as a source of RCC heritability and identifies several promising novel susceptibility genes, including , which warrant further investigation.

Impact: Our findings illustrate the value of pathway analysis as a complementary approach to analyzing GWAS data.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0472DOI Listing
October 2020

Patterns of racial/ethnic disparities in baseline health-related quality of life and relationship with overall survival in patients with colorectal cancer.

Qual Life Res 2020 Nov 3;29(11):2977-2986. Epub 2020 Jul 3.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose: Racial disparities are evident in colorectal cancer (CRC) prognosis with black patients experiencing worse outcomes than Hispanics and whites, yet mediators of these disparities are not fully known. The aim of this study is to identify variables that contribute to racial/ethnic disparities in health-related quality of life (HR-QoL) and overall survival in CRC.

Methods: Using SF-12 questionnaires, we assessed HR-QoL in 1132 CRC patients by calculating their physical (PCS) and mental composite summary (MCS) scores. Associations between poor PCS/MCS and sociodemographic factors were estimated and survival differences were identified by race/ethnicity.

Results: Hispanic patients who never married were at greater risk of poor PCS (OR 2.69; 95% CI 1.11-6.49; P = 0.028) than were currently married patients. College education was associated with a decreased risk of poor PCS in Hispanic and white, but not black, patients. Gender was significantly associated with poor MCS among white patients only. CRC patients who reported a poor PCS or MCS had poor survival, with differences in median survival times (MSTs) by race. The effect of PCS was strongest in white CRC patients with a difference in overall MST of > 116 months between those with favorable versus poor physical HR-QoL. Black patients who reported poor Physical and Mental HR-QoL showed significant risk of a poor outcome.

Conclusion: These findings suggest that racial/ethnic disparities in CRC survival may be related to differences in HR-QoL. Identified mediators of HR-QoL could supplement current CRC management strategies to improve patients' survival.
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http://dx.doi.org/10.1007/s11136-020-02565-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606765PMC
November 2020

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

Blood Adv 2020 06;4(12):2789-2797

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.
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http://dx.doi.org/10.1182/bloodadvances.2020001435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322948PMC
June 2020

Population-based targeted sequencing of 54 candidate genes identifies as a susceptibility gene for high-grade serous ovarian cancer.

J Med Genet 2021 May 16;58(5):305-313. Epub 2020 Jun 16.

Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Catalunya, Spain.

Purpose: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.

Methods: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.

Results: The ORs associated for high-grade serous ovarian cancer were 3.01 for (95% CI 1.59 to 5.68; p=0.00068), 1.99 for (95% CI 1.15 to 3.43; p=0.014) and 4.07 for (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for in high-grade serous ovarian cancer is likely to represent a true positive.

Conclusions: We have found strong evidence that carriers of deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
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http://dx.doi.org/10.1136/jmedgenet-2019-106739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086250PMC
May 2021

Perinatal depressive and anxiety symptoms of pregnant women during the coronavirus disease 2019 outbreak in China.

Am J Obstet Gynecol 2020 08 11;223(2):240.e1-240.e9. Epub 2020 May 11.

Ningbo Women and Children's Hospital, Ningbo, Zhejiang, China.

Background: On January 20, 2020, a new coronavirus epidemic with human-to-human transmission was officially declared by the Chinese government, which caused significant public panic in China. In light of the coronavirus disease 2019 outbreak, pregnant women may be particularly vulnerable and in special need for preventive mental health strategies. Thus far, no reports exist to investigate the mental health response of pregnant women to the coronavirus disease 2019 outbreak.

Objective: This study aimed to examine the impact of coronavirus disease 2019 outbreak on the prevalence of depressive and anxiety symptoms and the corresponding risk factors among pregnant women across China.

Study Design: A multicenter, cross-sectional study was initiated in early December 2019 to identify mental health concerns in pregnancy using the Edinburgh Postnatal Depression Scale. This study provided a unique opportunity to compare the mental status of pregnant women before and after the declaration of the coronavirus disease 2019 epidemic. A total of 4124 pregnant women during their third trimester from 25 hospitals in 10 provinces across China were examined in this cross-sectional study from January 1, 2020, to February 9, 2020. Of these women, 1285 were assessed after January 20, 2020, when the coronavirus epidemic was publicly declared and 2839 were assessed before this pivotal time point. The internationally recommended Edinburgh Postnatal Depression Scale was used to assess maternal depression and anxiety symptoms. Prevalence rates and risk factors were compared between the pre- and poststudy groups.

Results: Pregnant women assessed after the declaration of coronavirus disease 2019 epidemic had significantly higher rates of depressive symptoms (26.0% vs 29.6%, P=.02) than women assessed before the epidemic declaration. These women were also more likely to have thoughts of self-harm (P=.005). The depressive rates were positively associated with the number of newly confirmed cases of coronavirus disease 2019 (P=.003), suspected infections (P=.004), and deaths per day (P=.001). Pregnant women who were underweight before pregnancy, primiparous, younger than 35 years, employed full time, in middle income category, and had appropriate living space were at increased risk for developing depressive and anxiety symptoms during the outbreak.

Conclusion: Major life-threatening public health events such as the coronavirus disease 2019 outbreak may increase the risk for mental illness among pregnant women, including thoughts of self-harm. Strategies targeting maternal stress and isolation such as effective risk communication and the provision of psychological first aid may be particularly useful to prevent negative outcomes for women and their fetuses.
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http://dx.doi.org/10.1016/j.ajog.2020.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211756PMC
August 2020

Author Correction: Personalized Risk Assessment in Never, Light, and Heavy Smokers in a prospective cohort in Taiwan.

Sci Rep 2020 Mar 23;10(1):5514. Epub 2020 Mar 23.

UC San Diego Moores Cancer Center, San Diego, California, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-62322-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090032PMC
March 2020

Genetic variants in epithelial-mesenchymal transition genes as predictors of clinical outcomes in localized prostate cancer.

Carcinogenesis 2020 08;41(8):1057-1064

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Epithelial-mesenchymal transition (EMT) plays a pivotal role in the progression of prostate cancer (PCa). However, little is known about genetic variants in the EMT pathway as predictors of aggressiveness, biochemical recurrence (BCR) and disease reclassification in localized PCa.

Patients And Methods: In this multistage study, we evaluated 5186 single nucleotide polymorphisms (SNPs) from 264 genes related to EMT pathway to identify SNPs associated with PCa aggressiveness and BCR in the MD Anderson PCa (MDA-PCa) patient cohort (N = 1762), followed by assessment of the identified SNPs with disease reclassification in the active surveillance (AS) cohort (N = 392).

Results: In the MDA-PCa cohort, 312 SNPs were associated with high D'Amico risk (P < 0.05), among which, 14 SNPs in 10 genes were linked to BCR risk. In the AS cohort, 2 of 14 identified SNPs (rs76779889 and rs7083961) in C-terminal Binding Proteins 2 gene were associated with reclassification risk. The associations of rs76779889 with different endpoints were: D'Amico high versus low, odds ratio [95% confidence interval (CI)] = 2.89 (1.32-6.34), P = 0.008; BCR, hazard ratio (HR) (95% CI) = 2.88 (1.42-5.85), P = 0.003; and reclassification, HR (95% CI) = 2.83 (1.40-5.74), P = 0.004. For rs7083961, the corresponding risk estimates were: D'Amico high versus low, odds ratio (95% CI) = 1.69 (1.12-2.57), P = 0.013; BCR, HR (95% CI) = 1.87 (1.15-3.02), P = 0.011 and reclassification, HR (95% CI) = 1.72 (1.09-2.72), P = 0.020. There were cumulative effects of these two SNPs on modulating these endpoints.

Conclusion: Genetic variants in EMT pathway may influence the risks of localized PCa's aggressiveness, BCR and disease reclassification, suggesting their potential role in the assessment and management of localized PCa.
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http://dx.doi.org/10.1093/carcin/bgaa026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422619PMC
August 2020

Comprehensive T cell repertoire characterization of non-small cell lung cancer.

Nat Commun 2020 01 30;11(1):603. Epub 2020 Jan 30.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe, Houston, TX, 77030, USA.

Immunotherapy targeting T cells is increasingly utilized to treat solid tumors including non-small cell lung cancer (NSCLC). This requires a better understanding of the T cells in the lungs of patients with NSCLC. Here, we report T cell repertoire analysis in a cohort of 236 early-stage NSCLC patients. T cell repertoire attributes are associated with clinicopathologic features, mutational and immune landscape. A considerable proportion of the most prevalent T cells in tumors are also prevalent in the uninvolved tumor-adjacent lungs and appear specific to shared background mutations or viral infections. Patients with higher T cell repertoire homology between the tumor and uninvolved tumor-adjacent lung, suggesting a less tumor-focused T cell response, exhibit inferior survival. These findings indicate that a concise understanding of antigens and T cells in NSCLC is needed to improve therapeutic efficacy and reduce toxicity with immunotherapy, particularly adoptive T cell therapy.
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http://dx.doi.org/10.1038/s41467-019-14273-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992630PMC
January 2020

Soluble immune checkpoint-related proteins as predictors of tumor recurrence, survival, and T cell phenotypes in clear cell renal cell carcinoma patients.

J Immunother Cancer 2019 11 29;7(1):334. Epub 2019 Nov 29.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. With the exception of a few candidate biomarkers, the prognostic role of soluble immune checkpoint-related proteins in clear cell renal cell cancer (ccRCC) patients is largely uninvestigated.

Methods: We profiled the circulating levels of 14 immune checkpoint-related proteins panel (BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, Tim-3, CD28, CD80, CD137, CD27 and CTLA-4) and their associations with the risk of recurrence and death in 182 ccRCC patients using a multiplex Luminex assay. Gene expression in tumors from a subset of participating patients (n = 47) and another 533 primary ccRCC from TCGA were analyzed to elucidate potential mechanisms. Our primary endpoint is overall survival; secondary endpoint is recurrence-free survival. Multivariate Cox proportional hazard model, unconditional logistic regression model, and Kaplan-Meier analysis were applied in the study.

Results: sTIM3 and sLAG3 were significantly associated with advanced (stage III) disease (P < 0.05). sPD-L2 was the strongest predictor of recurrence (HR 2.51, 95%CI 1.46-4.34, P = 9.33E-04), whereas high sBTLA and sTIM3 was associated with decreased survival (HR 6.02, 95%CI 2.0-18.1, P = 1.39E-03 and HR 3.12, 95%CI 1.44-6.75, P = 3.94E-03, respectively). Risk scores based on sTIM3 and sBTLA indicated that the soluble immune checkpoint-related proteins jointly predicted recurrence and death risks of ccRCC (P = 0.01 and 4.44E-04, respectively). Moreover, sLAG3 and sCD28 were found negatively correlated with cytolytic activity of T cells in tumors (rho = -0.31 and - 0.33, respectively).

Conclusions: Our study provides evidence that soluble immune checkpoint-related proteins may associate with advanced disease, recurrence and survival in ccRCC patients, which highlights the prognostic values of soluble immune checkpoint-related proteins. Future independent validation in prospective studies is warranted.
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http://dx.doi.org/10.1186/s40425-019-0810-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884764PMC
November 2019

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways.

Hum Mol Genet 2020 01;29(1):70-79

Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.
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http://dx.doi.org/10.1093/hmg/ddz228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001601PMC
January 2020

Loss of Life Expectancy by 10 Years or More From Elevated Aspartate Aminotransferase: Finding Aspartate Aminotransferase a Better Mortality Predictor for All-Cause and Liver-Related than Alanine Aminotransferase.

Am J Gastroenterol 2019 09;114(9):1478-1487

Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.

Objectives: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are 2 commonly ordered liver function tests, and ALT has long been considered more liver-specific than AST. Between the 2, the one which is better in predicting liver or non-liver-related mortality remains unsettled.

Methods: The cohort, 416,122 adults, came from a self-paying comprehensive health surveillance program during 1994-2008 and was followed up till 2008. Mortality came from National Death Index, with 10,412 deaths identified. Hazard ratios (HRs), computed by Cox model, and life expectancy, by life table method, were presented for 5 levels of AST and ALT with elevated AST or ALT defined as ≥40 IU/L. Liver disease included liver cancer and other liver conditions.

Results: There were 3 times more elevated ALT (15.4%) than AST (5.7%). However, those with elevated AST had higher mortality for all-cause (HR = 2.44), for liver disease (HR = 27.2), and for liver cancer (HR = 47.6) than its ALT counterparts (HR = 1.69, 10.8, and 20.2, respectively). Elevated AST also lost more years of life expectancy (10.2) than those lost by ALT (5.2) and larger than most common risks. Elevated AST had increased mortality from all cancers (HR = 3.57), stroke (HR = 1.36), respiratory diseases (HR = 1.34), and injuries (HR = 1.82), other than just liver disease. All-cause mortality remained significantly increased, when high risk groups were excluded, such as frequent drinkers, hepatitis carriers, those died from nonmedical conditions, those died in the first 3 years, or advanced fibrosis index based on 4 factors or aspartate transaminase-to-platelet ratio index. Results were consistent between those returned for second visits and those analyzed in initial visits.

Discussion: Those with elevated AST (≥40 IU/L) had life expectancy cut short by 10.2 years, doubled the number of years lost with elevated ALT. For all-cause and for liver-related mortality, AST was an important predictor, better than ALT.
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http://dx.doi.org/10.14309/ajg.0000000000000332DOI Listing
September 2019
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