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Massively parallel sequencing and genome-wide copy number analysis revealed a clonal relationship in benign metastasizing leiomyoma.

ABSTRACT: Benign metastasizing leiomyoma (BML) is a rare disease entity typically presenting as multiple extrauterine leiomyomas associated with a uterine leiomyoma. It has been hypothesized that the extrauterine leiomyomata represent distant metastasis of the uterine leiomyoma. To date, the only molecular evidence supporting this hypothesis was derived from clonality analyses based on X-chromosome inactivation assays. Here, we sought to address this issue by examining paired specimens of synchronous pulmonary and uterine leiomyomata from three patients using targeted massively parallel sequencing and molecular inversion probe array analysis for detecting somatic mutations and copy number aberrations. We detected identical non-hot-spot somatic mutations and similar patterns of copy number aberrations (CNAs) in paired pulmonary and uterine leiomyomata from two patients, indicating the clonal relationship between pulmonary and uterine leiomyomata. In addition to loss of chromosome 22q found in the literature, we identified additional recurrent CNAs including losses of chromosome 3q and 11q. In conclusion, our findings of the clonal relationship between synchronous pulmonary and uterine leiomyomas support the hypothesis that BML represents a condition wherein a uterine leiomyoma disseminates to distant extrauterine locations.

SUBMITTER: Wu RC

PROVIDER: S-EPMC5564585 | biostudies-other | 2017 Jul

REPOSITORIES: biostudies-other

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Project description:BackgroundCancer re-sequencing programs rely on DNA isolated from fresh snap frozen tissues, the preparation of which is combined with additional preservation efforts. Tissue samples at pathology departments are routinely stored as formalin-fixed and paraffin-embedded (FFPE) samples and their use would open up access to a variety of clinical trials. However, FFPE preparation is incompatible with many down-stream molecular biology techniques such as PCR based amplification methods and gene expression studies.Methodology/principal findingsHere we investigated the sample quality requirements of FFPE tissues for massively parallel short-read sequencing approaches. We evaluated key variables of pre-fixation, fixation related and post-fixation processes that occur in routine medical service (e.g. degree of autolysis, duration of fixation and of storage). We also investigated the influence of tissue storage time on sequencing quality by using material that was up to 18 years old. Finally, we analyzed normal and tumor breast tissues using the Sequencing by Synthesis technique (Illumina Genome Analyzer, Solexa) to simultaneously localize genome-wide copy number alterations and to detect genomic variations such as substitutions and point-deletions and/or insertions in FFPE tissue samples.Conclusions/significanceThe application of second generation sequencing techniques on small amounts of FFPE material opens up the possibility to analyze tissue samples which have been collected during routine clinical work as well as in the context of clinical trials. This is in particular important since FFPE samples are amply available from surgical tumor resections and histopathological diagnosis, and comprise tissue from precursor lesions, primary tumors, lymphogenic and/or hematogenic metastases. Large-scale studies using this tissue material will result in a better prediction of the prognosis of cancer patients and the early identification of patients which will respond to therapy.

Project description:BackgroundPulmonary benign metastasizing leiomyoma (PBML) is the most common extrauterine spread of uterine leiomyoma, and its biological behavior is traditionally thought to be hormone dependent. Studies on older PBML patients have been previously reported, but limited literature has been published regarding the clinical features and treatment of PBML in young women.MethodsA total of 65 cases of PBML in women aged 45 years and younger were reviewed, including 56 cases selected from PubMed and 9 cases from our hospital. The clinical characteristics and management of these patients were analyzed.ResultsThe median age of all the patients at diagnosis was 39.0 years. PBML most commonly presented as bilateral solid lesions (60.9%), with other rare imaging manifestations. The median interval time from a pertinent gynecologic procedure to diagnosis was 6.0 years. A total of 16.7% of patients received careful observation, and all achieved stable status in a median follow-up time of 18.0 months. A total of 71.4% of patients were administered anti-estrogen therapies, including surgical castration (33.3%), gonadotropin-releasing hormone analog (23.8%) and anti-estrogen drugs (14.3%). Eight of 42 patients underwent surgical resection of metastatic lesions. Patients who underwent curative surgery for the removal of pulmonary lesions combined with adjuvant anti-estrogen therapies had favorable outcomes compared with those who only underwent surgical resection. The disease control rates of surgical castration, gonadotropin-releasing hormone analog, and anti-estrogen drugs were 85.7%, 90.0%, and 50.0%, respectively. For two patients, sirolimus (rapamycin) achieved successful relief of symptoms and control of pulmonary lesions without lowering hormone levels and causing estrogen deficiency symptoms.ConclusionsIn the absence of standard treatment guidelines for PBML, maintaining a low-estrogen environment using different kinds of antiestrogen therapies has been the mainstream strategy and has satisfying curative effects. A wait-and-see strategy might be an option, but therapeutic approaches must be contemplated when complications or symptoms progress. For PBML in young women, the negative effect on ovarian function of anti-estrogen treatment, especially surgical castration, should be considered. Sirolimus might be a new treatment option for young PBML patients, especially for those who want to preserve ovarian function.

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Massively parallel sequencing and genome-wide copy number analysis revealed a clonal relationship in benign metastasizing leiomyoma.

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