IMPORTANCE Pathogenic germline variants in the ATM gene have been associated with pancreatic cancer risk. Although genetic testing identifies these variants in approximately 1% to 3% of unselected patients with pancreatic cancer, the lifetime risk of pancreatic cancer among individuals with pathogenic ATM variants has not been well estimated. OBJECTIVE To estimate age-specific penetrance of pancreatic cancer in individuals with a pathogenic variant in the ATM gene. DESIGN, SETTING, AND PARTICIPANTS This was a multicenter cohort study of pancreatic cancer family registries in the US and Canada using pedigree data from 130 pancreatic cancer kindreds with a pathogenic germline ATM variant. Data analyses were performed from January 2020 to February 2021. MAIN OUTCOMES AND MEASURES Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis. RESULTS The study population of 130 families (123 [95%] White families) comprised 2227 family members (mean age [SD], 58 [22] years; 1096 [49%] women) with complete records (ie, including familial relationships, pancreatic cancer diagnosis, ATM status, proband status, and age), of which 155 individuals had positive results for an ATM pathogenic variant, 16 had a negative result, and the remainder did not have a test result. In these 130 families, 217 individuals had pancreatic cancer: 78 families had 1 such member; 34 families had 2 such members; and 18 families had 3 or more members with pancreatic cancer. The average (range) age at diagnosis was 64 (31-98) years. The cumulative risk of pancreatic cancer among individuals with a germline pathogenic ATM variant was estimated to be 1.1% (95% CI, 0.8%-1.3%) by age 50 years; 6.3% (95% CI, 3.9%-8.7%) by age 70 years; and 9.5% (95% CI, 5.0%-14.0%) by age 80 years. Overall, the relative risk of pancreatic cancer was 6.5 (95% CI, 4.5-9.5) in ATM variant carriers compared with noncarriers. CONCLUSIONS AND RELEVANCE This multicenter cohort study found that individuals with a germline pathogenic ATM variant were at an increased lifetime risk of pancreatic cancer. These risk estimates can help guide decision-making when evaluating the risks and benefits of enhanced early detection surveillance.

中文翻译：

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ATM基因致病性变异个体患胰腺癌的风险。

重要性 ATM 基因中的致病性种系变异与胰腺癌风险相关。尽管基因检测在大约 1% 到 3% 的未选择胰腺癌患者中发现了这些变异，但尚未很好地估计具有致病性 ATM 变异的个体患胰腺癌的终生风险。目的 估计 ATM 基因致病性变异个体中胰腺癌的年龄特异性外显率。设计、设置和参与者 这是一项针对美国和加拿大胰腺癌家族登记的多中心队列研究，使用来自 130 个具有致病性胚系 ATM 变异的胰腺癌家族的谱系数据。数据分析于 2020 年 1 月至 2021 年 2 月进行。主要结果和措施 观察胰腺癌的年龄特异性风险。使用改进的分离分析估计外显率。结果 130 个家庭（123 [95%] 白人家庭）的研究人群包括 2227 名家庭成员（平均年龄 [SD]，58 [22] 岁；1096 [49%] 女性），具有完整的记录（即，包括家庭关系、胰腺癌诊断、ATM 状态、先证者状态和年龄），其中 155 人的 ATM 致病性变异呈阳性结果，16 人的结果为阴性，其余的人没有检测结果。在这 130 个家庭中，有 217 人患有胰腺癌：78 个家庭有 1 人；34 个家庭有 2 个这样的成员；18个家庭有3个或更多成员患有胰腺癌。诊断时的平均（范围）年龄为 64（31-98）岁。具有胚系致病性 ATM 变异的个体中胰腺癌的累积风险估计为 1。50 岁时为 1%（95% CI，0.8%-1.3%）；70 岁时为 6.3%（95% CI，3.9%-8.7%）；到 80 岁时为 9.5%（95% CI，5.0%-14.0%）。总体而言，与非携带者相比，ATM 变异携带者患胰腺癌的相对风险为 6.5（95% CI，4.5-9.5）。结论和相关性 这项多中心队列研究发现，具有胚系致病性 ATM 变异的个体患胰腺癌的终生风险增加。在评估加强早期检测监测的风险和收益时，这些风险估计可以帮助指导决策。结论和相关性 这项多中心队列研究发现，具有胚系致病性 ATM 变异的个体患胰腺癌的终生风险增加。在评估加强早期检测监测的风险和收益时，这些风险估计可以帮助指导决策。结论和相关性 这项多中心队列研究发现，具有胚系致病性 ATM 变异的个体患胰腺癌的终生风险增加。在评估加强早期检测监测的风险和收益时，这些风险估计可以帮助指导决策。