1.Ferroptosis and osteoporosis
Cheng YANG ; Weimin LI ; Dongcheng RAN ; Jiamu XU ; Wangxiang WU ; Jiafu XU ; Jingjing CHEN ; Guangfu JIANG ; Chunqing WANG
Chinese Journal of Tissue Engineering Research 2025;29(3):554-562
BACKGROUND:It has also been confirmed that ferroptosis is closely related to a variety of musculoskeletal diseases,such as rheumatoid arthritis,osteosarcoma,and osteoporosis.The pathophysiological mechanisms of ferroptosis and osteoporosis need to be further studied and elucidated to broaden our understanding of iron metabolism and osteoporosis.It will provide research ideas for the future elucidation of new mechanisms of osteoporosis and the development of new technologies and drugs for the treatment of osteoporosis. OBJECTIVE:To provide an overview of the current status of research on ferroptosis in osteoporosis,to provide a new direction for future research on the specific molecular mechanisms of osteoporosis,and to provide more effective and better options for osteoporosis treatment strategies. METHODS:The first author used the computer to search the literature published from 2000 to 2024 in CNKI,WanFang,VIP,and PubMed databases with search terms"ferroptosis,iron metabolism,osteoporosis,osteoblast,osteoclast,bone metabolism,signal pathway,musculoskeletal,review"in Chinese and English.A total of 68 articles were finally included according to the selection criteria. RESULTS AND CONCLUSION:(1)Ferroptosis is a new type of cell death discovered in recent years,which is usually accompanied by a large amount of iron accumulation and lipid peroxidation during cell death,and its occurrence is iron-dependent.This is distinctly different from several types of cell death that are currently being hotly studied(e.g.,cellular pyroptosis,necrotic apoptosis,cuproptosis,and autophagy).(2)Intracellular iron homeostasis is manifested as a balance between iron uptake,export,utilization,and storage.The body's iron regulatory system includes systemic and intracellular regulation.The main factor of systemic regulation is hepcidin produced by hepatic secretion,and cellular regulation depends on the iron regulatory protein/iron response element system.Of course,intracellular iron homeostasis can be controlled by other factors,such as hypoxia,cytokines,and hormones.(3)Lipid peroxidation causes oxidative damage to biological membranes(plasma membrane and internal organelle membranes),lipoproteins,and other lipid-containing molecules.Polyunsaturated fatty acid-containing phospholipids are important targets of lipid peroxidation.Free polyunsaturated fatty acid is an important substrate for lipid oxidation and can bind to the phospholipid bilayer,leading to over-oxidation and thus triggering lipid apoptosis.(4)Several studies have shown that osteoblasts are overloaded with iron in different ways,resulting in the accumulation of unstable ferrous iron and the generation of reactive oxygen species and lipid peroxides,causing ferroptosis of osteoblasts and ultimately a decrease in bone formation,affecting bone homeostasis and the development of osteoporosis.(5)Osteoclasts are large multinucleated cells formed by the fusion of mononuclear macrophage cell lines or bone marrow mesenchymal stem cells induced by nuclear factor-κB ligand receptor activator,and they have the function of bone resorption.Iron ions can promote osteoclast differentiation and bone resorption through the production of intracellular lipid reactive oxygen species,while iron chelators can inhibit osteoclast formation in vitro and thus affect the occurrence and development of osteoporosis.
2.Improvement effect of velvet antler polypeptide in osteoporosis model rats and its effect on SIRT1/FOXO1 signaling pathway
Xueting CHI ; Xiaowei HUANG ; Fangyuan CHEN ; Gaofeng ZHOU ; Jinji WANG ; Guangfu LYU ; Zhe LIN ; Qing GONG
Journal of Jilin University(Medicine Edition) 2024;50(1):120-127
Objective:To discuss the protective effect of velvet antler peptide(VAP)in the osteoporosis(OP)model rats,and to clarify the possible mechanism.Methods:Sixty 12-week-old SD rats were randomly divided into control group,model group,positive drug group(treated with 1 mg·kg-1·d-1 of alendronate sodium by gavage),low dose of VAP group(treated with 100 mg·kg-1·d-1 VAP),medium dose of VAP group(treated with 200 mg·kg-1·d-1 VAP),and high dose of VAP group(treated with 300 mg·kg-1·d-1 VAP),and there were ten rats in each group.Except for control group,the rats in the other groups were injected with dexamethasone(2 mg·kg-1)to replicate the OP rat model,while the rats in control group were injected with the equivalent volume of saline twice a week for 11 consecutive weeks.Dual-energy X-ray absorptiometry was used to detect the bone mineral density(BMD)of femur tissue of the rats in various groups;enzyme-linked immunosorbent assay(ELISA)method was used to detect the levels of serum calcium(Ca2+),phosphate(P),osteoprotegerin(OPG),alkaline phosphatase(ALP),and osteocalcin(OCN)in serum of the rats in various groups;biochemical method was used to detect the malondialdehyde(MDA)level and superoxide dismutase(SOD)activity in serum of the rats in various groups;HE staining was used to observe the pathomorphology of bone tissue of the rats in various groups;Western blotting method was used to detect the expression levels of silent information regulator 1(SIRT1),catalase(CAT),Runt-related transcription factor 2(RUNX2),and forkhead box protein O1(FOXO1)proteins in bone tissue of the rats in various groups.Results:Compared with control group,the BMD of femoral tissue of the rats in model group was decreased(P<0.05);compared with model group,the BMD of femur tissue of the rats in positive drug group,medium dose of VAP group,and high dose of VAP group were increased(P<0.05 or P<0.01).Compared with control group,the levels of Ca2+,P,OPG,and SOD activities in serum of the rats in model group were decreased(P<0.05),and the levels of ALP,OCN,and MDA were increased(P<0.05);compared with model group,the level of OPG in serum of the rats in low dose of VAP group was significantly increased(P<0.05),the levels of Ca2+,P,OPG,and activities of SOD in serum of the rats in positive drug group,medium dose of VAP group,and high dose of VAP group were significantly increased(P<0.05 or P<0.01),and the levels of ALP,OCN,and MDA in serum of the rats in positive drug group and different doses of VAP groups were decreased(P<0.05 or P<0.01).The HE staining results showed that compared with control group,the rats in model group had fewer bone cells and disordered arrangements in the bone tissue,thinner bone trabeculae with large fractures,and an expanded marrow cavity;compared with model group,the rats in positive drug group,medium dose of VAP group,and high dose of VAP group had thicker bone trabeculae arranged more tightly.The Western blotting results showed that compared with control group,the expression levels of SIRT1,CAT,RUNX2,and FOXO1 proteins in bone tissue of the rats in model group were decreased(P<0.05);compared with model group,the expression levels of SIRT1,CAT,RUNX2,and FOXO1 proteins in bone tissue of the rats in positive drug group,medium dose of VAP group,and high dose of VAP group were significantly increased(P<0.05 or P<0.01).Conclusion:VAP has the protective effect against OP in the rats,and its mechanism may be related to mediating the antioxidant stress action through the SIRT1/FOXO1 signaling pathway.
3.Five-year survival analysis of gastric cancer from population-based cancer registration data in Zhejiang province, China
Huizhang LI ; Hongting ZHU ; Yaoyao CHEN ; Rongshou ZHENG ; Guangfu JIN ; Lingbin DU ; Xiangdong CHENG
Chinese Journal of Oncology 2024;46(9):862-870
Objective:To analyze epidemiology of gastric cancer five-year survival distribution in Zhejiang population-based cancer registration.Methods:The follow-up data of registrated gastric cancer cases diagnosed from 2008 to 2019 in 22 national cancer registry areas of Zhejiang Province were collected and divided into three diagnostic periods: 2008-2011, 2012-2015 and 2016-2019 to calculate five-year observed survival rates (OSRs), five-year relative survival rates (RSRs) and five-year age-standardized relative survival rates (ARSRs). The distribution of population characteristics (including gender, urban/rural, age group and occupation) and clinical characteristics (including the highest diagnostic institution, sub-site, pathological type and degree of differentiation) of gastric cancer survival rates in each period were analysed.Results:51 663 new cases of gastric cancer in 2008-2019 in the cancer registration area of Zhejiang Province were included in the analysis, and the ARSR of gastric cancer in 2008-2011, 2012-2015 and 2016-2019 showed an increasing trend (39.2%, 41.3% and 44.7%, respectively). In 2016-2019, the ARSR was similar across gender and urban and rural areas (44.4% for men and 45.7% for women; 44.9% in urban areas and 44.2% in rural areas); Among people with different occupations, the ARSR was highest among business and service workers (55.3%), the agriculture, forestry, animal husbandry and fisheries, water conservancy production workers and domestic workers were lower (41.5% and 43.2%, respectively). The highest diagnostic institution was the provincial hospital with a higher gastric cancer survival rate (47.0%) than the municipal (43.4%) and district (43.6%) levels. The ARSR for gastric cancer was relatively high in the lesser curvature (59.7%), pylorus (50.4%), antrum (49.3%), and greater curvature (48.7%), and lowest in cardia (38.9%). Among the major pathological types, adenocarcinoma (NOS) had an ARSR of 48.1%, mucinous adenocarcinoma 41.3%, imprinted cell carcinoma 39.4%, and squamous carcinoma 33.4%. The ARSR for highly differentiated, moderately differentiated, poorly differentiated and undifferentiated gastric cancers were 80.6%, 57.9%, 43.2% and 36.8%, respectively.Conclusion:The 5-year survival rate of gastric cancer in Zhejiang Province is high and on the rise, with similar survival rates in different genders, urban and rural areas, and significant differences in the survival rates of gastric cancer patients with different occupational groups, highest diagnostic institutions, tumour sub-sites, pathological types and differentiation degrees.
4.Five-year survival analysis of gastric cancer from population-based cancer registration data in Zhejiang province, China
Huizhang LI ; Hongting ZHU ; Yaoyao CHEN ; Rongshou ZHENG ; Guangfu JIN ; Lingbin DU ; Xiangdong CHENG
Chinese Journal of Oncology 2024;46(9):862-870
Objective:To analyze epidemiology of gastric cancer five-year survival distribution in Zhejiang population-based cancer registration.Methods:The follow-up data of registrated gastric cancer cases diagnosed from 2008 to 2019 in 22 national cancer registry areas of Zhejiang Province were collected and divided into three diagnostic periods: 2008-2011, 2012-2015 and 2016-2019 to calculate five-year observed survival rates (OSRs), five-year relative survival rates (RSRs) and five-year age-standardized relative survival rates (ARSRs). The distribution of population characteristics (including gender, urban/rural, age group and occupation) and clinical characteristics (including the highest diagnostic institution, sub-site, pathological type and degree of differentiation) of gastric cancer survival rates in each period were analysed.Results:51 663 new cases of gastric cancer in 2008-2019 in the cancer registration area of Zhejiang Province were included in the analysis, and the ARSR of gastric cancer in 2008-2011, 2012-2015 and 2016-2019 showed an increasing trend (39.2%, 41.3% and 44.7%, respectively). In 2016-2019, the ARSR was similar across gender and urban and rural areas (44.4% for men and 45.7% for women; 44.9% in urban areas and 44.2% in rural areas); Among people with different occupations, the ARSR was highest among business and service workers (55.3%), the agriculture, forestry, animal husbandry and fisheries, water conservancy production workers and domestic workers were lower (41.5% and 43.2%, respectively). The highest diagnostic institution was the provincial hospital with a higher gastric cancer survival rate (47.0%) than the municipal (43.4%) and district (43.6%) levels. The ARSR for gastric cancer was relatively high in the lesser curvature (59.7%), pylorus (50.4%), antrum (49.3%), and greater curvature (48.7%), and lowest in cardia (38.9%). Among the major pathological types, adenocarcinoma (NOS) had an ARSR of 48.1%, mucinous adenocarcinoma 41.3%, imprinted cell carcinoma 39.4%, and squamous carcinoma 33.4%. The ARSR for highly differentiated, moderately differentiated, poorly differentiated and undifferentiated gastric cancers were 80.6%, 57.9%, 43.2% and 36.8%, respectively.Conclusion:The 5-year survival rate of gastric cancer in Zhejiang Province is high and on the rise, with similar survival rates in different genders, urban and rural areas, and significant differences in the survival rates of gastric cancer patients with different occupational groups, highest diagnostic institutions, tumour sub-sites, pathological types and differentiation degrees.
5.Improvement effect of velvet antler polypeptide on postmenopausal osteoporosis in rats and its mechanism
Xueting CHI ; Fangyuan CHEN ; Zifeng PI ; Guangfu LYU ; Yuchen WANG ; Yinqing LI ; Xiaowei HUANG ; Zhe LIN
Journal of Jilin University(Medicine Edition) 2024;50(4):963-969
Objective:To discuss the protective effect of velvet antler peptide(VAP)on the postmenopausal osteoporosis(PMOP)model rats,and to clarify its possible mechanism.Methods:A total of 60 twelve-week-old female SD rats were randomly divided into sham operation group,model group,alendronate sodium group(1 mg·kg 1·d-1 alendronate sodium administered via gavage),low dose of VAP group(100 mg·kg·d-1 VAP administered via gavage),medium dose of VAP group(200 mg·kg 1·d-1 VAP administered via gavage),and high dose of VAP group(300 mg·kg1·d-1 VAP administered via gavage),and there were 10 rats in each group.Except for the sham operation group,the rats in the other groups underwent bilateral ovariectomy to establish the PMOP rat models.Dual-energy X-ray absorptiometry was used to detect the femur bone mineral density(BMD)of the rats in various groups;enzyme-linked immunosorbent assay(ELISA)was used to detect the levels of serum calcium(Ca2+),serum phosphorus(P),bone alkaline phosphatase(BALP),and procollagen type Ⅰ N-terminal propeptide(PINP)of the rats in various groups;Kits were used to detect the activities of superoxide dismutase(SOD)and the levels of malondialdehyde(MDA)of the rats in various groups;HE staining was used to observe the pathomorphology of bone tissue of the rats in various groups;Western blotting method was used to detect the expression levels of phosphatidylinositol 3-kinase(PI3K),phosphorylated PI3K(p-PI3K),protein kinase B(AKT),and phosphorylated AKT(p-AKT)proteins in bone tissue of the rats in various groups.Results:Compared with sham operation group,the BMD in femur of the rats in model group was decreased(P<0.01);compared with model group,the BMD in femur of the rats in alendronate sodium group,medium dose of VAP group,and high dose of VAP group was increased(P<0.05 or P<0.01).Compared with sham operation group,the levels of Ca2+,P,BALP,PINP,and SOD activity in serum of the rats in model group were decreased(P<0.05 or P<0.01),and the MDA level was increased(P<0.01);compared with model group,the level of P in serum of the rats in medium dose of VAP group was increased(P<0.01),and the levels of Ca2+,P,BALP,PINP and the activities of SOD in serum of the rats in alendronate sodium group and high dose of VAP group were increased(P<0.05 or P<0.01),and the level of MDA in serum was decreased(P<0.05).The HE staining results showed that compared with sham operation group,the bone trabeculae in bone tissue of the rats in model group were thin and fractured,and the medullary cavity was enlarged;compared with model group,the bone trabeculae in bone tissue of the rats in alendronate sodium group,medium dose of VAP group,and high dose of VAP group were thick and tightly arranged,and had more osteocytes.The Western blotting results showed that compared with sham operation group,the ratios of p-PI3K/PI3K and p-AKT/AKT in bone tissue of the rats in model group were decreased(P<0.01);compared with model group,the ratios of p-PI3K/PI3K in bone tissue of rats in different doses of VAP groups were increased(P<0.05 or P<0.01),and the ratios of p-AKT/AKT of the rats in alendronate sodium group and high dose of VAP group was increased(P<0.01).Conclusion:VAP can improve PMOP in the rats,and its mechanisms may be related to the regulation of the PI3K/AKT signaling pathway and the reduction of oxidative stress in bone tissue by VAP.
6.Microanatomy and functional MRI study of arcuate fasciculus and superior longitudinal fasciculus
Chen LI ; Guangfu DI ; Qiang LI ; Mingze TAN ; Jiakang HONG ; Kaiqiang DUAN ; Leilei MEI ; Yongsheng HE ; Xiaochun JIANG
Chinese Journal of Surgery 2023;61(11):1018-1023
Objectives:To explore the microanatomy and functional MRI(fMRI) of arcuate fasciculus(AF) and superior longitudinal fasciculus(SLF),and to analyze their functions.Methods:Ten normal adult cadaveric head specimens (20 cerebral hemispheres) were fixed with 10% methanal at the Translational Research Institute for Neurological Disorders of the Wannan Medical College from February to December 2022.The Klingler fiber dissection technique was utilized to perform white matter fiber dissection,with a magnification ranging from 6 to 40.The study focused on the microanatomical structures of the AF and SLF,aiming to explore their relationships with deep brain fibers.Furthermore, six healthy adult volunteers who underwent fMRI of the brain were included.The collected diffusion tensor imaging (DTI) data were processed and integrated with the microanatomical findings for a comprehensive analysis.Results:After removing the gray matter of the cerebral cortex,the superficial U fibers were exposed.The long association fibers that beneath the U fibers were the AF and SLF,which were the main long association fibers in the superficial layers of the brain.The AF could be divided into dorsal and ventral parts,while the SLF could be divided into Ⅰ,Ⅱ,and Ⅲ.SLF Ⅰ lied within the upper bank of the cingulate sulcus,travels medial to the callosal sulcus.The SLF Ⅱ,Ⅲ,and the AF were located on the lateral surface of the brain.By removing the gray matter of the insular cortex and the extreme capsule,exposing the external capsule and claustrum.Subsequently,the AF and SLF Ⅱ,Ⅲ were dissected,revealing the corona radiata and sagittal stratum,along with other deep brain fibers.During the dissection,it was observed that there was a close connection between the AF,SLF Ⅱ,and the deep brain fibers.Furthermore,in the regions above the lateral fissure of the cerebral hemisphere,there was no direct connection of long association fibers between the gray matter cortex and the deep U fibers in the coronal plane.These findings were further supported by DTI studies.Conclusions:The AF and SLF are the major long association fibers that located in the superficial layers of the brain,and closely connect to the gray matter cortex and U fibers,even closely relate with deep brain fibers.In the regions above the lateral fissure of the hemisphere,only the AF and SLF Ⅱ and Ⅲ serve as superficial long association fibers in the anterior-posterior direction.These fibers are likely involved in the transmission of brain functional information between the top and bottom gray matter cortex in the coronal plane above the lateral fissure.
7.Microanatomy and functional MRI study of arcuate fasciculus and superior longitudinal fasciculus
Chen LI ; Guangfu DI ; Qiang LI ; Mingze TAN ; Jiakang HONG ; Kaiqiang DUAN ; Leilei MEI ; Yongsheng HE ; Xiaochun JIANG
Chinese Journal of Surgery 2023;61(11):1018-1023
Objectives:To explore the microanatomy and functional MRI(fMRI) of arcuate fasciculus(AF) and superior longitudinal fasciculus(SLF),and to analyze their functions.Methods:Ten normal adult cadaveric head specimens (20 cerebral hemispheres) were fixed with 10% methanal at the Translational Research Institute for Neurological Disorders of the Wannan Medical College from February to December 2022.The Klingler fiber dissection technique was utilized to perform white matter fiber dissection,with a magnification ranging from 6 to 40.The study focused on the microanatomical structures of the AF and SLF,aiming to explore their relationships with deep brain fibers.Furthermore, six healthy adult volunteers who underwent fMRI of the brain were included.The collected diffusion tensor imaging (DTI) data were processed and integrated with the microanatomical findings for a comprehensive analysis.Results:After removing the gray matter of the cerebral cortex,the superficial U fibers were exposed.The long association fibers that beneath the U fibers were the AF and SLF,which were the main long association fibers in the superficial layers of the brain.The AF could be divided into dorsal and ventral parts,while the SLF could be divided into Ⅰ,Ⅱ,and Ⅲ.SLF Ⅰ lied within the upper bank of the cingulate sulcus,travels medial to the callosal sulcus.The SLF Ⅱ,Ⅲ,and the AF were located on the lateral surface of the brain.By removing the gray matter of the insular cortex and the extreme capsule,exposing the external capsule and claustrum.Subsequently,the AF and SLF Ⅱ,Ⅲ were dissected,revealing the corona radiata and sagittal stratum,along with other deep brain fibers.During the dissection,it was observed that there was a close connection between the AF,SLF Ⅱ,and the deep brain fibers.Furthermore,in the regions above the lateral fissure of the cerebral hemisphere,there was no direct connection of long association fibers between the gray matter cortex and the deep U fibers in the coronal plane.These findings were further supported by DTI studies.Conclusions:The AF and SLF are the major long association fibers that located in the superficial layers of the brain,and closely connect to the gray matter cortex and U fibers,even closely relate with deep brain fibers.In the regions above the lateral fissure of the hemisphere,only the AF and SLF Ⅱ and Ⅲ serve as superficial long association fibers in the anterior-posterior direction.These fibers are likely involved in the transmission of brain functional information between the top and bottom gray matter cortex in the coronal plane above the lateral fissure.
8.Cooperative work and mechanism in the COVID-19 containment action by the support-to-Hebei epidemiological investigation group formed by five provinces
Jinshui ZENG ; Meng ZHANG ; Wei ZHAO ; Weinan LI ; Guangfu ZENG ; Qiuling CHEN ; Tie SONG ; Huiming LUO
Shanghai Journal of Preventive Medicine 2022;34(11):1101-1105
ObjectiveTo understand the cooperative work and mechanism in the corona virus disease 2019 containment action by the support-to-Hebei epidemiological investigation group formed by five provinces, summarize the existing challenges, and discuss the relevant mechanism, so as to provide evidence for future support actions. MethodsA questionnaire survey was used to investigate the members from five provinces of the support-to-Hebei epidemiological investigation team. The content included basic information, work situation, problems in cooperative work, and suggestions in support mechanisms. ResultsA total of 104 questionnaires were issued, of which 101 valid questionnaires were collected with an effective response rate of 97.12%. The proportions of respondents who participated in the epidemic-related data preparation, case investigation, technical training, supervision of key venues, and specimen collection was 93.07%, 85.15%, 81.19%, 65.35%, and 44.55%, respectively. The respondents believed that information sharing channel of local epidemic situation was blocked (95.05%), coordination mechanism among local departments was insufficient (84.16%), communication and coordination mechanism among the dispatch institutions, support team, and local departments was unperfect (84.16%), management of the dispatch institutions to the support team was relatively loose (79.21%), dispatch institutions failed to make full use of professional advantages of the support team (72.28%), and majority of the support team members engaged in a single profession (59.41%). The respondents suggested that local departments should improve the information sharing mechanism (95.05%), strengthen communication and coordination among the dispatch institutions, support team, and local departments (92.08%), and dispatch institutions should clarify the tasks and responsibilities of the support team (91.09%), formulate cross-regional emergency support plans (87.13%) and evaluation plans of support action (72.28%). ConclusionIn order to ensure the efficiency and accuracy of future support actions, it is necessary to improve the mechanism of emergency coordination, communication and matching, response procedures, team management, and support evaluation.
9.Effect of scalp acupuncture on cognitive function and self-care ability of daily life in patients with traumatic brain injury.
Chinese Acupuncture & Moxibustion 2021;41(2):127-130
OBJECTIVE:
To observe the therapeutic effect of scalp acupuncture on cognitive dysfunction of traumatic brain injury.
METHODS:
Seventy patients with cognitive dysfunction of traumatic brain injury were randomly divided into an observation group and a control group, 35 cases in each group. After treatment, 5 cases dropped off in each group. The patients in the control group were treated with cognitive training; the patients in the observation group were treated with cognitive training and scalp acupuncture at Baihui (GV 20), Sishencong (EX-HN 1), Zhisanzhen and Niesanzhen, and the needles were retained for 6 h. The two groups were treated once a day, 6 times a week; one-month treatment was taken as one course, and 3 continuous courses were given. The scores of mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), activity of daily living (ADL) and functional independence measure (FIM) were compared between the two groups before and after treatment.
RESULTS:
Compared before treatment, the MMSE and MoCA scores in the observation group, and ADL and FIM scores in the two groups were significantly increased after treatment (
CONCLUSION
Scalp acupuncture could improve cognitive function and self-care ability of daily life in patients with traumatic brain injury.
Acupuncture Points
;
Acupuncture Therapy
;
Brain Injuries, Traumatic/therapy*
;
Cognition
;
Humans
;
Scalp
;
Self Care
10.Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.
Na QIN ; Yuancheng LI ; Cheng WANG ; Meng ZHU ; Juncheng DAI ; Tongtong HONG ; Demetrius ALBANES ; Stephen LAM ; Adonina TARDON ; Chu CHEN ; Gary GOODMAN ; Stig E BOJESEN ; Maria Teresa LANDI ; Mattias JOHANSSON ; Angela RISCH ; H-Erich WICHMANN ; Heike BICKEBOLLER ; Gadi RENNERT ; Susanne ARNOLD ; Paul BRENNAN ; John K FIELD ; Sanjay SHETE ; Loic LE MARCHAND ; Olle MELANDER ; Hans BRUNNSTROM ; Geoffrey LIU ; Rayjean J HUNG ; Angeline ANDREW ; Lambertus A KIEMENEY ; Shan ZIENOLDDINY ; Kjell GRANKVIST ; Mikael JOHANSSON ; Neil CAPORASO ; Penella WOLL ; Philip LAZARUS ; Matthew B SCHABATH ; Melinda C ALDRICH ; Victoria L STEVENS ; Guangfu JIN ; David C CHRISTIANI ; Zhibin HU ; Christopher I AMOS ; Hongxia MA ; Hongbing SHEN
Frontiers of Medicine 2021;15(2):275-291
Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
Adenocarcinoma of Lung/genetics*
;
Carcinoma, Non-Small-Cell Lung/genetics*
;
Carcinoma, Squamous Cell/genetics*
;
Genetic Heterogeneity
;
Genetic Predisposition to Disease
;
Genome-Wide Association Study
;
Humans
;
Lung Neoplasms/genetics*
;
Polymorphism, Single Nucleotide

Result Analysis
Print
Save
E-mail