The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. We identified 309 pathogenic variants among 4,850 variants in the 27 cancer-predisposing genes. Pathogenic variants in the following four cancer-predisposing genes were associated with a high risk of lymphoma: ATM (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.25–5.51; p = 1.06 × 10⁻²), BRCA1 (OR, 5.88; 95% CI, 2.65–13.02; p = 1.27 × 10⁻⁵), BRCA2 (OR, 2.94; 95% CI, 1.60–5.42; p = 5.25 × 10⁻⁴), and TP53 (OR, 5.22; 95% CI, 1.43–19.02; p = 1.23 × 10⁻²). The proportion of carriers of these genes was 1.6% of lymphoma patients. Furthermore, pathogenic variants in these genes were especially associated with a higher risk of mantle cell lymphoma (OR, 21.57; 95% CI, 7.59–61.26; p = 8.07 × 10⁻⁹). These results provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment, such as other neoplasms.

中文翻译：

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癌症易感基因中的种系致病变异与淋巴瘤风险之间的关联

先进分子技术的应用显着扩大了淋巴瘤分类，实现了风险分层和治疗优化。有限的证据表明淋巴瘤存在遗传易感性，表明基于新型淋巴瘤分类的更好个体化临床管理的潜力。在这里，我们检查了生殖系致病变异对 27 个具有淋巴瘤风险的癌症易感基因的影响，并探讨了致病变异携带者的临床特征。这项研究包括来自日本人群的 2,066 名淋巴瘤患者和 38,153 名无癌症对照。在对测序数据进行质量控制后，进一步分析了来自 1,982 名淋巴瘤患者和 37,592 名对照的样本。我们在 4 个中鉴定出 309 个致病变异，27 个癌症易感基因中的 850 个变体。以下四种癌症易感基因的致病变异与淋巴瘤的高风险相关：ATM（优势比 [OR]，2.63；95% 置信区间 [CI]，1.25–5.51；p  = 1.06 × 10 ^-2），BRCA1（OR，5.88；95% CI，2.65–13.02；p  = 1.27 × 10 ^-5）、BRCA2（OR，2.94；95% CI，1.60-5.42；p  = 5.25 × 10 ^-4）和TP53（OR，5.22；95% CI，1.43-19.02；p  = 1.23 × 10 ^-2） . 这些基因携带者的比例为淋巴瘤患者的1.6%。此外，这些基因的致病变异与套细胞淋巴瘤的高风险特别相关（OR，21.57；95% CI，7.59–61.26；p  = 8.07 × 10 ^-9）。这些结果为淋巴瘤分类的单基因形式提供了新的见解。一些淋巴瘤患者可能会受益于监测和靶向治疗，例如其他肿瘤。