Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland.
JAMA Oncol. 2021 Nov 1;7(11):1664-1668. doi: 10.1001/jamaoncol.2021.3701.
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.
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.
Observational age-specific risk of pancreatic cancer. Penetrance was estimated using modified segregation analysis.
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.
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.
ATM 基因中的致病性种系变异与胰腺癌风险相关。虽然基因检测在未选择的胰腺癌患者中约 1%至 3%识别出这些变异，但具有致病性 ATM 变异个体的胰腺癌终生风险尚未得到很好的估计。
估计携带 ATM 基因致病性变异个体的胰腺癌的年龄特异性外显率。
设计、地点和参与者：这是一项在美国和加拿大的胰腺癌家族登记处进行的多中心队列研究，使用来自 130 个具有致病性种系 ATM 变异的胰腺癌家系的系谱数据。数据分析于 2020 年 1 月至 2021 年 2 月进行。
观察性年龄特异性胰腺癌风险。使用改良分离分析估计外显率。
该研究人群由 130 个家族（123 个[95%]白人家庭）组成，共 2227 名家族成员（平均年龄[标准差]，58[22]岁；1096 名[49%]女性），记录完整（即包括家族关系、胰腺癌诊断、ATM 状态、先证者状态和年龄），其中 155 人具有 ATM 致病性变异阳性结果，16 人具有阴性结果，其余人没有检测结果。在这 130 个家族中，217 人患有胰腺癌：78 个家族有 1 个成员；34 个家族有 2 个成员；18 个家族有 3 个或更多成员患有胰腺癌。平均（范围）诊断年龄为 64（31-98）岁。通过年龄 50 岁时估计个体携带种系致病性 ATM 变异的胰腺癌累积风险为 1.1%（95%CI，0.8%-1.3%）；70 岁时为 6.3%（95%CI，3.9%-8.7%）；80 岁时为 9.5%（95%CI，5.0%-14.0%）。总体而言，与非携带者相比，ATM 变异携带者的胰腺癌风险相对增加 6.5（95%CI，4.5-9.5）。
这项多中心队列研究发现，具有种系致病性 ATM 变异的个体患胰腺癌的终生风险增加。这些风险估计可以帮助指导评估增强早期检测监测的风险和益处时的决策。
