Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eur Urol. 2023 Jan;83(1):29-38. doi: 10.1016/j.eururo.2022.08.028. Epub 2022 Sep 15.
Tumor-only genomic profiling is an important tool in therapeutic management of men with prostate cancer. Since clinically actionable germline variants may be reflected in tumor profiling, it is critical to identify which variants have a higher risk of being germline in origin to better counsel patients and prioritize genetic testing.
To determine when variants found on tumor-only sequencing of prostate cancers should prompt confirmatory germline testing.
DESIGN, SETTING, AND PARTICIPANTS: Men with prostate cancer who underwent both tumor and germline sequencing at Memorial Sloan Kettering Cancer Center from January 1, 2015 to January 31, 2020 were evaluated.
Tumor and germline profiles were analyzed for pathogenic and likely pathogenic ("pathogenic") variants in 60 moderate- or high-penetrance genes associated with cancer predisposition. The germline probability (germline/germline + somatic) of a variant was calculated for each gene. Clinical and pathologic factors were analyzed as potential modifiers of germline probability.
Of the 1883 patients identified, 1084 (58%) had a somatic or germline pathogenic variant in one of 60 cancer susceptibility genes, and of them, 240 (22%) had at least one germline variant. Overall, the most frequent variants were in TP53, PTEN, APC, BRCA2, RB1, ATM, and CHEK2. Variants in TP53, PTEN, or RB1 were identified in 746 (40%) patients and were exclusively somatic. Variants with the highest germline probabilities were in PALB2 (69%), MITF (62%), HOXB13 (60%), CHEK2 (55%), BRCA1 (55%), and BRCA2 (47%), and the overall germline probability of a variant in any DNA damage repair gene was 40%. Limitations were that most of the men included in the cohort had metastatic disease, and different thresholds for pathogenicity exist for somatic and germline variants.
Of patients with pathogenic variants found on prostate tumor sequencing, 22% had clinically actionable germline variants, for which the germline probabilities varied widely by gene. Our results provide an evidenced-based clinical framework to prioritize referral to genetic counseling following tumor-only sequencing.
Patients with advanced prostate cancer are recommended to have germline genetic testing. Genetic sequencing of a patient's prostate tumor may also identify certain gene variants that are inherited. We found that patients who had variants in certain genes, such as ones that function in DNA damage repair, identified in their prostate tumor sequencing, had a high risk for having an inherited cancer syndrome.
肿瘤基因组分析是管理男性前列腺癌的重要工具。由于临床相关的种系变异可能反映在肿瘤分析中，因此确定哪些变异更有可能来源于种系，以便更好地为患者提供咨询并优先进行基因检测至关重要。
确定何时应进行前列腺癌肿瘤测序中发现的变异的确认性种系检测。
设计、地点和参与者：评估了 2015 年 1 月 1 日至 2020 年 1 月 31 日期间在纪念斯隆凯特琳癌症中心同时进行肿瘤和种系测序的男性前列腺癌患者。
分析了与癌症易感性相关的 60 个中度或高度外显率基因中与致病性和可能致病性（“致病性”）变体相关的肿瘤和种系图谱。为每个基因计算了变异的种系概率（种系/种系+体细胞）。分析了临床和病理因素作为种系概率的潜在修饰因子。
在确定的 1883 名患者中，1084 名（58%）在 60 个癌症易感性基因中的一个中具有体细胞或种系致病性变异，其中 240 名（22%）至少有一种种系变异。总体而言，最常见的变异发生在 TP53、PTEN、APC、BRCA2、RB1、ATM 和 CHEK2 中。TP53、PTEN 或 RB1 中的变异在 746 名（40%）患者中被发现，且均为体细胞。具有最高种系概率的变异发生在 PALB2（69%）、MITF（62%）、HOXB13（60%）、CHEK2（55%）、BRCA1（55%）和 BRCA2（47%）中，任何 DNA 损伤修复基因中的变异的总体种系概率为 40%。局限性在于，该队列中的大多数男性均患有转移性疾病，并且体细胞和种系变异的致病性存在不同的阈值。
在接受前列腺肿瘤测序的患者中，有 22%的患者发现了致病性变异，这些变异的种系概率因基因而异。我们的结果为肿瘤测序后推荐进行遗传咨询提供了基于证据的临床框架。
患有晚期前列腺癌的患者被建议进行种系基因检测。对患者前列腺肿瘤的基因测序也可能会识别出某些遗传的基因变异。我们发现，在肿瘤测序中发现特定基因（例如参与 DNA 损伤修复的基因）中的变异的患者，具有遗传癌症综合征的高风险。
