Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors.
Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors.
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DOI：
10.1371/journal.pone.0142487
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Parker BA
中科院分区：
文献类型：
--
作者：
Bao L;Messer K;Schwab R;Harismendy O;Pu M;Crain B;Yost S;Frazer KA;Rana B;Hasteh F;Wallace A;Parker BA
同步性肿瘤可以是独立的原发性肿瘤，也可以是原发性-转移性（克隆）对，这可能具有临床意义。肿瘤DNA的突变谱在临床上越来越常见。我们研究了突变谱是否可以独立于乳腺癌和其他癌症中的克隆肿瘤进行区分，使用基于克隆Likestival评分的仔细定义的测试（CLS = 100 x共享高置信度（HC）突变数/总HC突变数）。使用CLS的正式测试的统计特性进行了研究。高CLS是支持克隆性的证据;该检验作为比例的单侧二项式检验实施。使用癌症基因组图谱，使用来自10种癌症类型的16，422个独立的乳腺肿瘤对和15个原发性转移性肿瘤对凭经验确定测试参数。我们使用五个已发表的数据集验证了该测试的性能，这些数据集包括15，758个已知的独立肿瘤对（最大CLS = 4.1%，最小p值= 0.48）和283个已知的肿瘤克隆对（最小CLS 13%，最大p值<0.01），横跨肾细胞癌，睾丸癌和结直肠癌。CLS测试正确分类了所有验证样品，但有一个样品似乎在发布的数据中被错误分类。作为概念验证，我们随后将CLS测试应用于我们机构的两个新的浸润性同步双侧乳腺癌病例，每个病例均具有一个激素受体阳性（ER+/PR+/HER 2-）小叶和一个三阴性导管癌。通过外显子组测序鉴定高置信度突变，并使用深度靶向测序验证结果。第一肿瘤对具有81%的CLS（p值< 10-15），支持克隆性。在第二对中，没有验证184个变体的常见突变（p值>0.99），支持独立性。在克隆对中确定了从激素受体阳性转变为三阴性的合理分子机制。我们已经从肿瘤DNA的突变谱中开发了一种仔细定义的克隆Likestrant评分测试的统计特性。在确定的条件下，该测试似乎可以可靠地区分几种癌症类型中的克隆性和独立起源的同步肿瘤。这种方法可能具有科学和临床实用性。
Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal) pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC) mutations/ # total HC mutations). Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas. We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48) and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value <0.01), across renal cell, testicular, and colorectal cancer. The CLS test correctly classified all validation samples but one, which it appears may have been incorrectly classified in the published data. As proof-of-concept we then applied the CLS test to two new cases of invasive synchronous bilateral breast cancer at our institution, each with one hormone receptor positive (ER+/PR+/HER2-) lobular and one triple negative ductal carcinoma. High confidence mutations were identified by exome sequencing and results were validated using deep targeted sequencing. The first tumor pair had CLS of 81% (p-value < 10–15), supporting clonality. In the second pair, no common mutations of 184 variants were validated (p-value >0.99), supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the clonal pair. We have developed the statistical properties of a carefully defined Clonal Likelihood Score test from mutational profiling of tumor DNA. Under identified conditions, the test appears to reliably distinguish between synchronous tumors of clonal and of independent origin in several cancer types. This approach may have scientific and clinical utility.