Brock Pamela L, Webster Morgan, Liyanarachchi Sandya, Byrne Lindsey, Hedges Dale J, Gulhati Pat, Hicks J Kevin, Chan Carlos H F, Onel Kenan, Stout Leigh Anne, Maxwell Whitney, Pickarski Justine Cooper, Estrada-Veras Juvianee, Salhia Bodour, Axell Lisen, Holman Laura L, Abdel-Rahman Mohamed H, Ringel Matthew D
Division of Human Genetics, The Ohio State University College of Medicine, Comprehensive Cancer Center, Columbus, OH.
Maternal Fetal Medicine, Legacy Health, Portland, OR.
JCO Precis Oncol. 2025 Jul;9:e2400946. doi: 10.1200/PO-24-00946. Epub 2025 Jul 9.
Germline likely pathogenic and pathogenic variants (LPV/PVs) in have been associated with an increased risk of various cancers including angiosarcoma, melanoma, glioma, thyroid cancer, and chronic lymphocytic leukemia (CLL). However, to date, most of the published data regarding PVs involve cohorts of patients selected for specific cancer types, or stem from commercial laboratory cohorts from patients selected for germline clinical testing, which may cause ascertainment biases. The objective was to identify germline variants in a pan-cancer cohort and describe the associated phenotypes.
Germline exome data available for 19,315 patients with cancer from the Oncology Research Information Exchange Network (ORIEN) were assessed for LPV/PV. Data regarding cancer diagnoses were obtained for those with and without variants. Associations were assessed.
LPV/PVs were identified in 23 patients. The cancer types seen in more than one patient include CLL (n = 7), papillary thyroid cancer (PTC, n = 5), colorectal cancer (n = 3), lung cancer (n = 3), glioblastoma (n = 2), and neuroendocrine tumors (n = 2). Compared with -negative patients, those with LPV/PVs were 5.5-fold more likely to be diagnosed with PTC (95% CI, 1.9 to 15.1; = .004) and 16.6-fold more likely to be diagnosed with CLL (95% CI, 6.4 to 41.9; < .001). Patients with LPV/PVs had a younger median age of first cancer diagnosis compared with -negative patients ( = .008).
To our knowledge, this study is the largest investigation of germline variants in a pan-cancer cohort. We identify and confirm specific associations with CLL and PTC in this cohort. Differences in results between analysis of largely unselected cohorts compared with clinical testing cohorts highlight the need to study gene-cancer associations in more unselected populations.
[基因名称]中的胚系可能致病性和致病性变异（LPV/PV）与包括血管肉瘤、黑色素瘤、胶质瘤、甲状腺癌和慢性淋巴细胞白血病（CLL）在内的多种癌症风险增加相关。然而，迄今为止，大多数已发表的关于[基因名称]PVs的数据涉及为特定癌症类型选择的患者队列，或源于为胚系临床检测选择的患者的商业实验室队列，这可能会导致确诊偏倚。目的是在泛癌队列中识别胚系[基因名称]变异并描述相关表型。
对来自肿瘤学研究信息交换网络（ORIEN）的19315例癌症患者的胚系外显子数据进行[基因名称]LPV/PV评估。获取有和没有[基因名称]变异患者的癌症诊断数据。评估相关性。
在23例患者中鉴定出LPV/PV。不止1例患者出现的癌症类型包括CLL（n = 7）、乳头状甲状腺癌（PTC，n = 5）、结直肠癌（n = 3）、肺癌（n = 3）、胶质母细胞瘤（n = 2）和神经内分泌肿瘤（n = 2）。与[基因名称]阴性患者相比，有[基因名称]LPV/PV的患者被诊断为PTC的可能性高5.5倍（95%CI，1.9至15.1；P = .004），被诊断为CLL的可能性高16.6倍（95%CI，6.4至41.9；P < .001）。与[基因名称]阴性患者相比，有[基因名称]LPV/PV的患者首次癌症诊断的中位年龄更年轻（P = .008）。
据我们所知，本研究是对泛癌队列中[基因名称]胚系变异的最大规模调查。我们在该队列中识别并确认了与CLL和PTC的特定关联。与临床检测队列相比，在很大程度上未选择的队列分析结果的差异凸显了在更多未选择人群中研究基因与癌症关联的必要性。
