Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations.
Lin Guo-Wang,Xu Caigang,Chen Kexin,Huang Hui-Qiang,Chen Jieping,Song Bao,Chan John K C,Li Wenyu,Liu Weiping,Shih Lee-Yung,Chuang Wen-Yu,Kim Won Seog,Tan Wen,Peng Rou-Jun,Laurensia Yurike,Cheah Daryl Ming Zhe,Huang DaChuan,Cheng Chee Leong,Su Yi-Jiun,Tan Soo-Yong,Ng Siok-Bian,Tang Tiffany Pooi Ling,Han Kyudong,Wang Vivien Ya-Fan,Jia Wei-Hua,Pei Zhong,Li Ya-Jun,Gao Song,Shi Yongyong,Hu Zhibin,Zhang Furen,Zhang Ben,Zeng Yi-Xin,Shen Hongbing,He Lin,Ong Choon Kiat,Lim Soon Thye,Chanock Stephen,Kwong Yok-Lam,Lin Dongxin,Rothman Nathaniel,Khor Chiea Chuen,Lan Qing,Bei Jin-Xin,
The Lancet. Oncology
BACKGROUND:Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS:We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS:Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION:Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING:Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.
Quantitative assessment of pulmonary function in lymphangioleiomyomatosis patients using high-resolution computed tomography and pulmonary function tests.
Ni Zhiwen,Ng Thomas S C,Liu Jie,Huang Suidan,Li Xiaoling,Xu Xiaoyin,Chen Huai
Journal of thoracic disease
Background:To explore the feasibility of using quantitative high-resolution computed tomography (HRCT) to evaluate pulmonary function in patients with pulmonary lymphangioleiomyomatosis (PLAM). Methods:Pulmonary function tests (PFTs) were performed in 30 patients with pathologically confirmed PLAM with the use of HRCT. These results were correlated with quantitative HRCT in 21 patients. Results:There were significant correlations between the HRCT parameters for lung function and PFT parameters. Among these parameters, emphysema volume (EV), pulmonary volume with a pixel index less than the trigger threshold (-950 HU) to account for a proportion of total lung volume [PI-950 (%)] and forced expiratory volume in 1 second/forced vital capacity [FEV1/FVC (%)] had the strongest correlations, reaching values between -0.71 and -0.68. HRCT lung function might therefore also be helpful for predicting changes in lung function before and after treatment. Conclusions:HRCT is helpful for the assessment of pulmonary function in PLAM patients and can assist in the clinical evaluation of lung function and treatment response in patients with this disease.
Mutation spectrums of TSC1 and TSC2 in Chinese women with lymphangioleiomyomatosis (LAM).
Liu Jie,Zhao Weiwei,Ou Xiaohua,Zhao Zhen,Hu Changming,Sun Mingming,Liu Feifei,Deng Junhao,Gu Weili,An Jiaying,Zhang Qingling,Zhang Xiaoxian,Xie Jiaxing,Li Shiyue,Chen Rongchang,Yu Shihui,Zhong Nanshan
The aim of our study was to elucidate the landscapes of genetic alterations of TSC1 and TSC2 as well as other possible non-TSC1/2 in Lymphangioleiomyomatosis (LAM) patients. Sixty-one Chinese LAM patients' clinical information was collected. Tumor biopsies and matched leukocytes from these patients were retrospectively analyzed by next generation sequencing (NGS), chromosomal microarray analysis (CMA), and multiplex ligation-dependent probe amplification (MLPA). Eighty-six TSC1/2 variants were identified in 46 of the 61 LAM patients (75.4%) in which TSC2 and TSC1 variants were 88.37% and 11.63% respectively. The 86 variants are composed of (i) 52 single nucleotide variants (SNVs) (including 30 novel variants), (ii) 23 indels (including 21deletions, and 2 insertions), (iii) a germline duplication of exon 31-42 of TSC2, (iv) a 2.68 Mb somatic duplication containing TSC2, and (v) 9 regions with copy-neutral loss of heterogeneity (CN-LOHs) present only in the LAM patients with single TSC1/2 mutations. Sixty-one non-TSC1/2 variants in 31 genes were identified in 37 LAM patients. Combined applications of different techniques are necessary to achieve maximal detection rate of TSC1/2 variants in LAM patients. Thirty novel TSC1/2 variants expands the spectrum of TSC1/2 in LAM patients. Identification of 61 non-TSC1/2 variants suggests that alternative genes might have contributed to the initiation and progression of LAM.