Zhang Dengfeng, Li Jing, Lu Tianxing, Zhao Fangchao, Guo Pengfei, Li Zhirong, Duan Xiaoliang, Li Yishuai, Li Shujun, Li Jianhang
Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Thoracic Surgery, Hebei Chest Hospital, Shijiazhuang, China.
J Cancer. 2024 Mar 4;15(8):2412-2423. doi: 10.7150/jca.92899. eCollection 2024.
Lung cancer and oesophageal cancer are prevalent malignancies with rising incidence and mortality worldwide. While some environmental and behavioural risk factors for these cancers are established, the contribution of genetic factors to their pathogenesis remains incompletely defined. This study aimed to interrogate the intricate genetic relationship between lung cancer and oesophageal cancer and their potential comorbidity. We utilised linkage disequilibrium score regression (LDSC) to analyse the genetic correlation between oesophageal carcinoma and lung carcinoma. We then employed several approaches, including pleiotropic analysis under the composite null hypothesis (PLACO), multi-marker analysis of genomic annotation (MAGMA), cis-expression quantitative trait loci (eQTL) analysis, and a pan-cancer assessment to identify pleiotropic loci and genes. Finally, we performed bidirectional Mendelian randomisation (MR) to evaluate the causal relationship between these malignancies. LDSC revealed a significant genetic correlation between oesophageal carcinoma and lung carcinoma. Further analysis identified shared gene loci including PGBD1, ZNF323, and WNK1 using PLACO. MAGMA identified enriched pathways and 9 pleiotropic genes including HIST1H1B, HIST1H4L, and HIST1H2BL. eQTL analysis integrating oesophageal, lung, and blood tissues revealed 26 shared genes including TERT, NKAPL, RAD52, BTN3A2, GABBR1, CLPTM1L, and TRIM27. A pan-cancer exploration of the identified genes was undertaken. MR analysis showed no evidence for a bidirectional causal relationship between oesophageal carcinoma and lung carcinoma. This study provides salient insights into the intricate genetic links between lung carcinoma and oesophageal carcinoma. Utilising multiple approaches for genetic correlation, locus and gene analysis, and causal assessment, we identify shared genetic susceptibilities and regulatory mechanisms. These findings reveal new leads and targets to further elucidate the genetic basis of lung and oesophageal carcinoma, aiding development of preventive and therapeutic strategies.
肺癌和食管癌是全球发病率和死亡率不断上升的常见恶性肿瘤。虽然这些癌症的一些环境和行为风险因素已明确，但遗传因素在其发病机制中的作用仍未完全明确。本研究旨在探究肺癌和食管癌之间复杂的遗传关系及其潜在的合并症。我们利用连锁不平衡评分回归（LDSC）分析食管癌和肺癌之间的遗传相关性。然后，我们采用了多种方法，包括复合零假设下的多效性分析（PLACO）、基因组注释的多标记分析（MAGMA）、顺式表达定量性状位点（eQTL）分析以及泛癌评估，以识别多效性位点和基因。最后，我们进行了双向孟德尔随机化（MR）以评估这些恶性肿瘤之间的因果关系。LDSC显示食管癌和肺癌之间存在显著的遗传相关性。进一步分析使用PLACO确定了包括PGBD1、ZNF323和WNK1在内的共享基因位点。MAGMA确定了富集的通路和9个多效性基因，包括HIST1H1B、HIST1H4L和HIST1H2BL。整合食管、肺和血液组织的eQTL分析揭示了26个共享基因，包括TERT、NKAPL、RAD52、BTN3A2、GABBR1、CLPTM1L和TRIM27。对已识别基因进行了泛癌探索。MR分析未显示食管癌和肺癌之间存在双向因果关系的证据。本研究为肺癌和食管癌之间复杂的遗传联系提供了重要见解。通过使用多种方法进行遗传相关性、位点和基因分析以及因果评估，我们识别了共享的遗传易感性和调控机制。这些发现揭示了新的线索和靶点，以进一步阐明肺癌和食管癌的遗传基础，有助于预防和治疗策略的开发。
