Isaacsson Velho Pedro, Silberstein John L, Markowski Mark C, Luo Jun, Lotan Tamara L, Isaacs William B, Antonarakis Emmanuel S
Johns Hopkins Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.
Prostate. 2018 Apr;78(5):401-407. doi: 10.1002/pros.23484. Epub 2018 Jan 25.
Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA-repair gene mutations, to facilitate selection of patients for germline testing.
We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical-grade assay (Color Genomics). This platform utilizes next-generation sequencing from saliva to interrogate 30 cancer-susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA-sequence alterations (pathogenic or variants) were offered genetic counseling.
Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation-positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines.
Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening.
介导DNA修复的基因中的胚系突变在复发性和晚期前列腺癌男性中很常见，其存在可能会改变预后和治疗方案。我们旨在确定与胚系DNA修复基因突变相关的病理和临床特征，以帮助选择进行胚系检测的患者。
我们回顾性评估了150例未经选择的复发性或转移性前列腺癌患者，这些患者由一名肿瘤学家使用临床级检测方法（Color Genomics）进行胚系基因检测。该平台利用唾液的下一代测序来检测30个癌症易感基因。有害胚系突变的存在与否与组织学和临床特征以及癌症家族史相关。所有DNA序列改变（致病性或变异）的患者都接受了遗传咨询。
在2016年7月至2017年7月期间，150例连续患者接受了胚系检测；在21名男性（14%）中发现了致病性突变。在那些有胚系突变的患者中，9例（43%）在BRCA2基因，3例（14%）在ATM基因，3例（14%）在CHEK2基因，2例（9%）在BRCA1基因。虽然胚系突变与年龄、肿瘤分期、 Gleason评分或家族史之间没有关联；但突变阳性患者在诊断时的中位PSA水平较低（5.5对8.6 ng/mL，P = 0.01），且具有独特的病理特征。具体而言，有胚系突变的男性更有可能具有导管内/导管组织学（48%对12%，P < 0.01）和淋巴血管侵犯（52%对14%，P < 0.01）。最后，根据当前的美国国立综合癌症网络（NCCN）指南，44%的胚系检测呈阳性的患者不会被提供基因筛查。
导管内/导管组织学和淋巴血管侵犯的存在似乎与前列腺癌男性的致病性胚系DNA修复基因突变相关，识别这些特征可能有助于选择进行胚系检测的患者。NCCN指南在预测哪些前列腺癌患者应接受基因筛查方面可能不够充分。
