Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.
Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.
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DOI：
10.1186/s13073-018-0595-5
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发表时间：
2018-11-21
期刊：
影响因子：
12.3
通讯作者：
Lindberg J
中科院分区：
文献类型：
--
作者：
Mayrhofer M;De Laere B;Whitington T;Van Oyen P;Ghysel C;Ampe J;Ost P;Demey W;Hoekx L;Schrijvers D;Brouwers B;Lybaert W;Everaert E;De Maeseneer D;Strijbos M;Bols A;Fransis K;Oeyen S;van Dam PJ;Van den Eynden G;Rutten A;Aly M;Nordström T;Van Laere S;Rantalainen M;Rajan P;Egevad L;Ullén A;Yachnin J;Dirix L;Grönberg H;Lindberg J
转移性前列腺癌有多种现有和新兴的治疗途径，其共同点是需要预测性生物标志物。循环肿瘤DNA（ctDNA）有可能以经济高效的方式加速精准医学试验，以提高临床疗效并降低成本和毒性。然而，迄今为止，转移性前列腺癌中的全面ctDNA分析是有限的。对来自217名转移性前列腺癌患者的364份血液样本中的血浆游离DNA和匹配的白色血细胞生殖系DNA进行靶向和低通全基因组测序的组合。在85.9%的基线样本中检测到ctDNA，与治疗线相关，并通过同步血液样本的循环肿瘤细胞计数反映。雄激素受体（AR）的综合分析显示，AR内结构变异的患者比例持续增加，从一线转移性去势抵抗性前列腺癌治疗期间的15.4%增加到四线治疗期间的45.2%，表明AR在疾病过程中持续演变。患者显示DNA修复缺陷基因的频繁改变（18.0%）。此外，在3.81%的合格样本（≥ 0.1 ctDNA分数）中鉴定出微卫星不稳定表型。对PTEN、RB 1和TP 53的非重复内含子和外显子区域进行测序，分别在ctDNA分数≥ 0.2的样本中检测到47.5%、20.3%和44.1%的双等位基因失活。只有一名患者携带克隆高影响变体，而没有可检测到的第二次命中。内含子高影响力的结构变异是常见的外显子突变的两倍，在PTEN和RB 1。最后，14.6%的患者由于克隆造血而出现假阳性变异，这在市售检测中通常被忽略。ctDNA图谱似乎反映了转移性前列腺癌组织的基因组景观，并且可以在旨在鉴定预测性生物标志物的临床试验中经济有效地提供体细胞信息。然而，询问的肿瘤抑制因子的内含子测序挑战了普遍关注的编码区，并且与同步白色血细胞的分析一起是至关重要的，以最大限度地减少错误的分配，这反过来可能混淆结果并阻碍临床试验中的真实关联。本文的在线版本（10.1186/s13073-018-0595-5）包含补充材料，可供授权用户使用。
There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials. The online version of this article (10.1186/s13073-018-0595-5) contains supplementary material, which is available to authorized users.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
28.2
作者：
Goodall J;Mateo J;Yuan W;Mossop H;Porta N;Miranda S;Perez-Lopez R;Dolling D;Robinson DR;Sandhu S;Fowler G;Ebbs B;Flohr P;Seed G;Rodrigues DN;Boysen G;Bertan C;Atkin M;Clarke M;Crespo M;Figueiredo I;Riisnaes R;Sumanasuriya S;Rescigno P;Zafeiriou Z;Sharp A;Tunariu N;Bianchini D;Gillman A;Lord CJ;Hall E;Chinnaiyan AM;Carreira S;de Bono JS;TOPARP-A investigators
通讯作者：
TOPARP-A investigators
影响因子：
23.4
作者：
Barbieri, Christopher E.;Chinnaiyan, Arul M.;Lerner, Seth P.;Swanton, Charles;Rubin, Mark A.
通讯作者：
Rubin, Mark A.
循环肿瘤DNA的体外稳定性。
影响因子：
3.7
作者：
Henao Diaz E;Yachnin J;Grönberg H;Lindberg J
通讯作者：
Lindberg J
影响因子：
23.4
作者：
De laere, Bram;van Dam, Pieter-Jan;Lindberg, Johan
通讯作者：
Lindberg, Johan