Przybyl Joanna, Spans Lien, Lum Deirdre A, Zhu Shirley, Vennam Sujay, Forgó Erna, Varma Sushama, Ganjoo Kristen, Hastie Trevor, Bowen Raffick, Debiec-Rychter Maria, van de Rijn Matt
Stanford University School of Medicine, Stanford, CA.
KU Leuven and University Hospitals Leuven, Leuven, Belgium.
JCO Precis Oncol. 2019;3. doi: 10.1200/po.18.00409. Epub 2019 Oct 16.
The preoperative distinction between uterine leiomyoma (LM) and leiomyosarcoma (LMS) is difficult, which may result in dissemination of an unexpected malignancy during surgery for a presumed benign lesion. An assay based on circulating tumor DNA (ctDNA) could help in the preoperative distinction between LM and LMS. This study addresses the feasibility of applying the two most frequently used approaches for detection of ctDNA: profiling of copy number alterations (CNAs) and point mutations in the plasma of patients with LM.
By shallow whole-genome sequencing, we prospectively examined whether LM-derived ctDNA could be detected in plasma specimens of 12 patients. Plasma levels of lactate dehydrogenase, a marker suggested for the distinction between LM and LMS by prior studies, were also determined. We also profiled 36 LM tumor specimens by exome sequencing to develop a panel for targeted detection of point mutations in ctDNA of patients with LM.
We identified tumor-derived CNAs in the plasma DNA of 50% (six of 12) of patients with LM. The lactate dehydrogenase levels did not allow for an accurate distinction between patients with LM and patients with LMS. We identified only two recurrently mutated genes in LM tumors ( and ).
Our results show that LMs do shed DNA into the circulation, which provides an opportunity for the development of ctDNA-based testing to distinguish LM from LMS. Although we could not design an LM-specific panel for ctDNA profiling, we propose that the detection of CNAs or point mutations in selected tumor suppressor genes in ctDNA may favor a diagnosis of LMS, since these genes are not affected in LM.
子宫平滑肌瘤（LM）与平滑肌肉瘤（LMS）的术前鉴别诊断存在困难，这可能导致在对假定为良性病变进行手术时意外的恶性肿瘤扩散。基于循环肿瘤DNA（ctDNA）的检测方法有助于LM与LMS的术前鉴别。本研究探讨了应用两种最常用的ctDNA检测方法的可行性：拷贝数改变（CNA）分析和LM患者血浆中的点突变检测。
通过浅层全基因组测序，我们前瞻性地检测了12例患者血浆样本中是否能检测到源自LM的ctDNA。还测定了乳酸脱氢酶的血浆水平，先前的研究表明该指标可用于区分LM和LMS。我们还通过外显子组测序对36个LM肿瘤标本进行分析，以开发一个用于靶向检测LM患者ctDNA中点突变的检测板。
我们在50%（12例中的6例）的LM患者血浆DNA中鉴定出肿瘤来源的CNA。乳酸脱氢酶水平无法准确区分LM患者和LMS患者。我们在LM肿瘤中仅鉴定出两个反复突变的基因（ 和 ）。
我们的结果表明，LM确实会向循环中释放DNA，这为开发基于ctDNA的检测方法以区分LM和LMS提供了机会。尽管我们无法设计出用于ctDNA分析的LM特异性检测板，但我们建议检测ctDNA中选定肿瘤抑制基因的CNA或点突变可能有助于LMS的诊断，因为这些基因在LM中不受影响。
