Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death.
Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death.
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DOI：
10.7554/elife.37294
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发表时间：
2018-09-04
期刊：
影响因子：
7.7
通讯作者：
Sawyers CL
中科院分区：
文献类型：
--
作者：
Hieronymus H;Murali R;Tin A;Yadav K;Abida W;Moller H;Berney D;Scher H;Carver B;Scardino P;Schultz N;Taylor B;Vickers A;Cuzick J;Sawyers CL
肿瘤基因组中的拷贝数改变（CNA）水平（称为CNA负荷）与原发性前列腺癌的复发相关。CNA负荷是否与前列腺癌生存率或其他癌症的结局相关尚不清楚。我们分析了活检和经尿道切除术队列中保守治疗前列腺癌的CNA情况，反映了越来越常见的治疗方法。我们发现，CNA负荷是癌症特异性死亡的预后指标，独立于标准的临床预测指标。更广泛地说，我们发现CNA负荷与TCGA队列中原发性乳腺癌、子宫内膜癌、肾透明细胞癌、甲状腺癌和结直肠癌的无病生存率和总生存率显著相关。为了评估临床适用性，我们在一个独立的泛癌症患者队列中验证了这些发现，这些患者的肿瘤使用临床认证的下一代测序测定法（MSK-IMPACT）进行测序，其中预后值根据癌症类型而变化。这种预后相关性受到某些队列中肿瘤纯度的影响。总体而言，原发性和转移性肿瘤的CNA负荷是一个预后因素，可能受样本纯度调节，并可通过当前临床测序进行测量。癌细胞携带不同类型的突变，这些突变与细胞开始不受控制地繁殖有关。某些变化只影响遗传密码的一个或几个字母。其他的，被称为拷贝数改变，或CNA，涉及基因组的较大部分，可以丢失（缺失）或复制（扩增）。不同患者的肿瘤携带不同数量的这些缺失或扩增，它们一起被称为CNA负荷。新技术使科学家能够扫描肿瘤的基因组，并检查每个患者中存在的突变类型。结果可以帮助决定最佳行动方案。例如，在前列腺癌中，肿瘤CNA负荷高的患者在治疗后复发的风险更大。然而，目前还不清楚这些人是否也有较低的生存率，以及CNA负担是否可以预测其他类型癌症的结果。Hierryus等人对来自未接受手术或放射治疗的前列腺癌患者的100多个样本进行了遗传分析。结果表明，肿瘤中较高的CNA负荷与疾病导致的更多死亡相关。前列腺癌的发现在不同类型的癌症中也是如此。这些结论也出现在Hierkalus等人使用不同的DNA测序测试从各种癌症患者中获得的基因组数据中，该测试已被认证用于临床使用。这表明CNA负荷可能是临床环境中帮助评估癌症患者风险的有用标志物。
The level of copy number alteration (CNA), termed CNA burden, in the tumor genome is associated with recurrence of primary prostate cancer. Whether CNA burden is associated with prostate cancer survival or outcomes in other cancers is unknown. We analyzed the CNA landscape of conservatively treated prostate cancer in a biopsy and transurethral resection cohort, reflecting an increasingly common treatment approach. We find that CNA burden is prognostic for cancer-specific death, independent of standard clinical prognosticators. More broadly, we find CNA burden is significantly associated with disease-free and overall survival in primary breast, endometrial, renal clear cell, thyroid, and colorectal cancer in TCGA cohorts. To assess clinical applicability, we validated these findings in an independent pan-cancer cohort of patients whose tumors were sequenced using a clinically-certified next generation sequencing assay (MSK-IMPACT), where prognostic value varied based on cancer type. This prognostic association was affected by incorporating tumor purity in some cohorts. Overall, CNA burden of primary and metastatic tumors is a prognostic factor, potentially modulated by sample purity and measurable by current clinical sequencing. Cancer cells carry different types of mutations that are associated with the cell starting to multiply uncontrollably. Certain changes only affect one or a few letters of the genetic code. Others, known as copy number alterations, or CNA, involve larger portions of the genome that can either be lost (deletions) or duplicated (amplifications). Tumors in different patients carry variable amounts of these deletions or amplifications, which together are known as the CNA burden. New technologies allow scientists to scan the genomes of tumors and examine the type of mutations present in each patient. The results can help to decide on the best course of action. For example, in prostate cancer, patients whose tumors have a high CNA burden are at greater risk of relapse after treatment. However, it has been unclear whether these people also have lower survival rates, and if CNA burden can predict outcome of other types of cancers. Hieronymus et al. conducted genetic analyses on over a hundred samples from prostate cancer patients who were not treated with surgery or radiation. The results showed that a higher CNA burden in the tumors is correlated with more deaths due to the disease. The findings in prostate cancer were also true across different types of cancers. These conclusions also emerged when Hieronymus et al. then looked at genomic data obtained from patients with various cancers using a different DNA sequencing test, which is certified for clinical use. This demonstrates that CNA burden could be a useful marker in clinical settings to help assess risk in cancer patients.