We investigated the prevalence of rare inherited pathogenic variants (PV) in 19 cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and their association with the risk of lymphoid malignancies (LM) overall and by common lymphoma subtypes and multiple myeloma. The study population included newly diagnosed LM cases (N = 6990) and unrelated controls (N = 42,632), excluding individuals with a history of hematologic malignancy. Whole exome sequencing was performed on DNA from whole blood. PV were defined as loss-of-function (i.e., nonsense, frameshift, consensus splice sites) or identified as “pathogenic” or “likely pathogenic” in the ClinVar database. A total of 1816 (3.7%) individuals had a PV across the 19 genes, higher in cases (4.7%) than controls (3.5%). In controls, CHEK2 (1.0%), ATM (0.4%), BRCA2 (0.4%), and BRCA1 (0.3%) had the highest prevalence. ATM (odds ratio [OR] = 1.86, 95% confidence interval [CI]: 1.36–2.49), CHEK2 (OR = 1.74, 95% CI: 1.42–2.13) and TP53 (OR = 9.07, 95% CI: 4.51–18.87) were associated with increased risk of LM overall and were further validated in the UK Biobank. We observed heterogeneity in associations by LM subtype. These results demonstrate that several commonly tested cancer predisposition genes are associated with an increased risk of LM.
我们调查了19个癌症易感基因中罕见遗传性致病性变异（PV）的流行情况——这些基因根据NCCN指南常规包含在多基因panel检测中——及其与总体淋巴恶性肿瘤（LM）风险以及常见淋巴瘤亚型和多发性骨髓瘤风险之间的关联。研究人群包括新诊断的LM病例（N=6990）和无关对照个体（N=42,632），排除了有血液系统恶性肿瘤病史者。对全血DNA进行了全外显子组测序。PV定义为功能丧失性变异（即无义、移码、保守剪接位点变异）或在ClinVar数据库中标记为"致病性"或"可能致病性"的变异。在19个基因中，共有1816名（3.7%）个体携带PV，病例组（4.7%）高于对照组（3.5%）。对照组中CHEK2（1.0%）、ATM（0.4%）、BRCA2（0.4%）和BRCA1（0.3%）的PV流行率最高。ATM（比值比[OR]=1.86，95%置信区间[CI]：1.36–2.49）、CHEK2（OR=1.74，95% CI：1.42–2.13）和TP53（OR=9.07，95% CI：4.51–18.87）与总体LM风险升高相关，并在UK Biobank中进一步验证。我们观察到不同LM亚型的关联存在异质性。这些结果表明，多个常规检测的癌症易感基因与LM风险增加相关。
Risk of lymphoid malignancy associated with cancer predisposition genes
肿瘤(癌症)患者之家