少数癌症患者对治疗的反应非常好，并且比具有类似诊断的患者存活时间明显更长。对生存时间极长的特殊反应者 (ER) 患者的种系遗传背景进行分析，可以深入了解影响治疗反应的种系多态性。由于 ER 在自身免疫性疾病中的发病率很高，我们假设自身免疫性疾病风险的差异可以反映 ER 的免疫背景，并有助于更好的癌症治疗反应。我们使用多基因风险评分 (PRS) 分析分析了 51 个 ER 的种系变异。与典型的癌症患者相比，ER 的几种自身免疫相关疾病的 PRS 显着升高：1 型糖尿病、甲状腺功能减退症和牛皮癣。这表明这些自身免疫性疾病的遗传易感性增加在 ER 中更为普遍。相比之下，ER 发生炎症性肠病的 PRS 明显较低。 1 型糖尿病评分的左偏对于特殊反应者来说非常显着。 T1D PRS 模型中与癌症药物反应相关的基因变异更有可能与 ER 中的其他变异同时出现。总之，与典型癌症患者相比，ER 表现出不同的自身免疫性疾病风险，这表明患者免疫设定点或免疫监视特异性的变化可能是其异常反应的潜在机制联系。这些发现扩展了之前针对接受免疫检查点抑制剂治疗的患者的研究，将接受化疗或放疗的患者纳入其中。© 2024。作者。

A small number of cancer patients respond exceptionally well to therapies and survive significantly longer than patients with similar diagnoses. Profiling the germline genetic backgrounds of exceptional responder (ER) patients, with extreme survival times, can yield insights into the germline polymorphisms that influence response to therapy. As ERs showed a high incidence in autoimmune diseases, we hypothesized the differences in autoimmune disease risk could reflect the immune background of ERs and contribute to better cancer treatment responses. We analyzed the germline variants of 51 ERs using polygenic risk score (PRS) analysis. Compared to typical cancer patients, the ERs had significantly elevated PRSs for several autoimmune-related diseases: type 1 diabetes, hypothyroidism, and psoriasis. This indicates that an increased genetic predisposition towards these autoimmune diseases is more prevalent among the ERs. In contrast, ERs had significantly lower PRSs for developing inflammatory bowel disease. The left-skew of type 1 diabetes score was significant for exceptional responders. Variants on genes involved in the T1D PRS model associated with cancer drug response are more likely to co-occur with other variants among ERs. In conclusion, ERs exhibited different risks for autoimmune diseases compared to typical cancer patients, which suggests that changes in a patient's immune set point or immune surveillance specificity could be a potential mechanistic link to their exceptional response. These findings expand upon previous research on immune checkpoint inhibitor-treated patients to include those who received chemotherapy or radiotherapy.© 2024. The Author(s).