The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. Individuals aged 40–80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a Familial Cancer Service since enrolment, with a further 21 kindreds identified as being suitable for reassessment. Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.

中文翻译：

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澳大利亚胰腺癌筛查计划参与者中显着检测到新种系致病变异

澳大利亚胰腺癌筛查计划 (APCSP) 为胰腺导管腺癌 (PDAC) 风险较高的个体提供内窥镜超声监测，所有参与者在参加研究之前或之后都需要接受家庭癌症服务机构的评估。年龄 40-80 岁（或比最早的 PDAC 诊断年轻 10 岁）的个体有资格参加 APCSP 研究，如果他们有 1) ≥ 2 名血亲患有 PDAC（至少有一个一级关联）；2) 遗传性胰腺炎或黑斑息肉综合征的临床或基因诊断，无论 PDAC 家族史如何；3) 已知的 PDAC 易感种系致病性变异（BRCA2、PALB2、CDKN2A 或 Lynch 综合征），且有 ≥ 1 名受 PDAC 影响的一级或二级亲属。对 2011 年 1 月至 2019 年 12 月在参与的澳大利亚医院登记的 APCSP 参与者进行了回顾性病历审查。我们审核了多个家族癌症服务机构提供的基因调查，这些服务根据国家指南、当地临床方案和/或可用性对 APCSP 参与者进行了评估外部研究资助的测试以及随后的发现。使用 Microsoft Excel 进行描述性统计分析。在 189 个亲属（285 名参与者）中，50 个亲属（71 名参与者）在入组时具有已知的种系致病性变异（BRCA2 n = 35、PALB2 n = 6、CDKN2A n = 3、STK11 n = 3、PRSS1 n = 2、MLH1 n = 1). 对 136 个没有已知种系致病变异的亲属中的 48 个（35%）进行了突变分析；89% 是诊所资助的，自 2016 年以来自费检测不断增加。进行基因检测的比率相对较低，反映出诊所资助的基因检测最初的严格标准。研究入组后，在 5 个家族 (10.4%) 中检测到新的种系致病变异（BRCA2 n = 3 个家族、PALB2 n = 1、CDKN2A n = 1）。值得注意的是，自注册以来，只有 8 个亲属接受了家庭癌症服务中心的重新评估，另有 21 个亲属被确定适合重新评估。在我们的高风险队列中，29.1% 的人发现了与 PDAC 相关的种系致病变异（55/189 亲属；82/285 名参与者）。重要的是，接受基因检测的亲属中，有 10.4% 新发现具有种系致病变异，其中大多数是 BRCA2。随着 PDAC 基因检测标准的迅速发展，家庭癌症服务中心每 5 年对高风险个体进行一次重新评估是有必要的。