ImportanceBreast cancers (BCs) diagnosed between 2 screening examinations are called interval cancers (ICs), and they have worse clinicopathological characteristics and poorer prognosis than screen-detected cancers (SDCs). However, the association of rare germline genetic variants with IC have not been studied.ObjectiveTo evaluate whether rare germline deleterious protein-truncating variants (PTVs) can be applied to discriminate between IC and SDC while considering mammographic density.Design, Setting, and ParticipantsThis population-based genetic association study was based on women aged 40 to 76 years who were attending mammographic screening in Sweden. All women with a diagnosis of BC between January 2001 and January 2016 were included, together with age-matched controls. Patients with BC were followed up for survival until 2021. Statistical analysis was performed from September 2021 to December 2022.ExposureGermline PTVs in 34 BC susceptibility genes as analyzed by targeted sequencing.Main Outcomes and MeasuresOdds ratios (ORs) were used to compare IC with SDC using logistic regression. Hazard ratios were used to investigate BC-specific survival using Cox regression.ResultsAll 4121 patients with BC (IC, n = 1229; SDC, n = 2892) were female, with a mean (SD) age of 55.5 (7.1) years. There were 5631 age-matched controls. The PTVs of the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes were more common in patients with IC compared with SDC (OR, 1.48; 95% CI, 1.06-2.05) and associated with BRCA1/2 and PALB2 variants. A family history of BC together with PTVs of any of these genes synergistically increased the probability of receiving a diagnosis of IC rather than SDC (OR, 3.95; 95% CI, 1.97-7.92). Furthermore, 10-year BC-specific survival revealed that if a patient received a diagnosis of an IC, carriers of PTVs in any of these 5 genes had significantly worse survival compared with patients not carrying any of them (hazard ratio, 2.04; 95% CI, 1.06-3.92). All of these associations were further pronounced in a subset of patients with IC who had a low mammographic density at prior screening examination.Conclusions and RelevanceThe results of this study may be helpful in future optimizations of screening programs that aim to lower mortality as well as the clinical treatment of patients with BC.

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与间期乳腺癌相关的基因改变的调查

重要性在两次筛查检查之间诊断出的乳腺癌（BC）称为间隔癌（IC），与筛查检测到的癌症（SDC）相比，它们具有更差的临床病理特征和更差的预后。然而，罕见种系遗传变异与 IC 的关联尚未研究。目的评估罕见种系有害蛋白截短变异 (PTV) 是否可用于区分 IC 和 SDC，同时考虑乳房 X 线摄影密度。设计、设置和参与者此人群基于遗传关联的研究以在瑞典参加乳房 X 光检查的 40 至 76 岁女性为对象。2001 年 1 月至 2016 年 1 月期间所有被诊断为 BC 的女性以及年龄匹配的对照组均被纳入研究。对 BC 患者的生存情况进行随访直至 2021 年。从 2021 年 9 月至 2022 年 12 月进行统计分析。通过靶向测序分析 34 个 BC 易感基因中的 ExposureGermline PTV。主要结果和测量比值比 (OR) 用于比较 IC 与 SDC使用逻辑回归。使用 Cox 回归，利用风险比来研究 BC 特异性生存率。结果 所有 4121 名 BC 患者（IC，n = 1229；SDC，n = 2892）均为女性，平均 (SD) 年龄为 55.5 (7.1) 岁。有 5631 名年龄匹配的对照者。PTV 的自动提款机,乳腺癌1,BRCA2,查克2， 和PALB2与 SDC 患者相比，这些基因在 IC 患者中更为常见（OR，1.48；95% CI，1.06-2.05），并且与乳腺癌1/2和PALB2变体。BC 家族史与任何这些基因的 PTV 一起协同增加了诊断为 IC 而不是 SDC 的可能性（OR，3.95；95% CI，1.97-7.92）。此外，10 年 BC 特异性生存率显示，如果患者被诊断为 IC，则与不携带任何基因的患者相比，携带这 5 种基因中任何一种的 PTV 的患者的生存率显着较差（风险比，2.04；95%） CI，1.06-3.92）。所有这些关联在先前筛查检查时乳房 X 光密度较低的 IC 患者亚群中进一步明显。结论和相关性本研究的结果可能有助于未来优化旨在降低死亡率和死亡率的筛查计划。 BC患者的临床治疗。