Departments of Biomarker Discovery, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Mod Pathol. 2017 Sep;30(9):1223-1233. doi: 10.1038/modpathol.2017.52. Epub 2017 Jun 23.
Sporadic lymphangioleiomyomatosis is a progressive pulmonary cystic disease resulting from the infiltration of smooth muscle-like lymphangioleiomyomatosis cells into the lung. The migratory/metastasizing properties of the lymphangioleiomyomatosis cell together with the presence of somatic mutations, primarily in the tuberous sclerosis complex gene (TSC2), lead many to consider this a low-grade malignancy. As malignant tumors characteristically accumulate somatic structural variations, which have not been well studied in sporadic lymphangioleiomyomatosis, we utilized mate pair sequencing to define structural variations within laser capture microdissected enriched lymphangioleiomyomatosis cell populations from five sporadic lymphangioleiomyomatosis patients. Lymphangioleiomyomatosis cells were confirmed in each tissue by hematoxylin eosin stain review and by HMB-45 immunohistochemistry in four cases. A mutation panel demonstrated characteristic TSC2 driver mutations in three cases. Genomic profiles demonstrated normal diploid coverage across all chromosomes, with no aneuploidy or detectable gains/losses of whole chromosomal arms typical of neoplastic diseases. However, somatic rearrangements and smaller deletions were validated in the two cases which lacked TSC2 driver mutations. Most significantly, one of these sporadic lymphangioleiomyomatosis cases contained two different size deletions encompassing the entire TSC1 locus. The detection of a homozygous deletion of TSC1 driving a predicted case of sporadic lymphangioleiomyomatosis, consistent with the common two-hit TSC2 mutation model, has never been reported for sporadic lymphangioleiomyomatosis. However, while no evidence of the hereditary tuberous sclerosis complex disease was reported for this patient, the potential for mosaicism and sub-clinical phenotype cannot be ruled out. Nevertheless, this study demonstrates that somatic structural rearrangements are present in lymphangioleiomyomatosis disease and provides a novel method of genomic characterization of sporadic lymphangioleiomyomatosis cells, aiding in defining cases with no detected mutations by conventional methodologies. These structural rearrangements could represent additional pathogenic mechanisms in sporadic lymphangioleiomyomatosis disease, potentially affecting response to therapy and adding to the complex genetic story of this rare disease.
散发性淋巴管平滑肌瘤病是一种进行性肺囊性疾病，由平滑肌样淋巴管平滑肌瘤病细胞浸润肺部引起。淋巴管平滑肌瘤病细胞的迁移/转移特性以及体细胞突变的存在，主要是在结节性硬化症复合物基因（TSC2）中，导致许多人将其视为低度恶性肿瘤。由于恶性肿瘤通常会积累体细胞结构变异，而这些变异在散发性淋巴管平滑肌瘤病中尚未得到很好的研究，我们利用配对末端测序来定义来自五个散发性淋巴管平滑肌瘤病患者的激光捕获显微解剖富集淋巴管平滑肌瘤病细胞群体中的结构变异。在四例中，通过苏木精-伊红染色和 HMB-45 免疫组化证实了每个组织中的淋巴管平滑肌瘤病细胞。突变面板在三例中显示出典型的 TSC2 驱动突变。基因组谱显示所有染色体均为正常二倍体覆盖，没有肿瘤疾病典型的非整倍体或整个染色体臂的可检测增益/缺失。然而，在两个缺乏 TSC2 驱动突变的病例中，验证了体细胞重排和较小的缺失。最重要的是，其中一个散发性淋巴管平滑肌瘤病病例包含两个不同大小的缺失，涵盖整个 TSC1 基因座。TSC1 的纯合缺失导致预测的散发性淋巴管平滑肌瘤病病例的检测，与常见的 TSC2 突变二击模型一致，从未报道过散发性淋巴管平滑肌瘤病。然而，尽管该患者未报告遗传性结节性硬化症疾病的证据，但不能排除镶嵌和亚临床表型的可能性。然而，这项研究表明，体细胞结构重排存在于淋巴管平滑肌瘤病中，并提供了一种新的散发性淋巴管平滑肌瘤病细胞基因组特征分析方法，有助于确定通过传统方法未检测到突变的病例。这些结构重排可能代表散发性淋巴管平滑肌瘤病中的额外致病机制，可能影响治疗反应，并增加这种罕见疾病的复杂遗传故事。
