IsomiRs and tRNA-derived fragments are associated with metastasis and patient survival in uveal melanoma.
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ABSTRACT:
SUBMITTER: Londin E
PROVIDER: S-EPMC6928426 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
IsomiRs and tRNA-derived fragments are associated with metastasis and patient survival in uveal melanoma.
Londin Eric E Magee Rogan R Shields Carol L CL Lally Sara E SE Sato Takami T Rigoutsos Isidore I
Pigment cell & melanoma research 20190816 1
Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults. With over 50% of patients developing metastatic disease, there is an unmet need for improved diagnostic and therapeutic options. Efforts to understand the molecular biology of the disease have revealed several markers that correlate with patient prognosis, including the copy number of chromosome 3, genetic alterations in the BAP1, EIF1AX and SF3B1 genes, and other transcriptional features. Here, we expand upon prev ...[more]
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Project description:BackgroundMetastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice.ResultsBy using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice.ConclusionsSurgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies.
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Project description:Uveal melanoma (UM) is a major intraocular cancer that is molecularly distinct from cutaneous melanoma. Approximately half of patients with UM eventually develop metastasis. The prognosis of metastatic UM is poor, with a median overall survival (OS) of less than a year. In this study, we sought to identify microRNAs (miRNAs) associated with metastasis and OS in UM. We analyzed the miRNA expression and clinical outcomes data from The Cancer Genome Atlas (TCGA) dataset for UM. Differential expression analyses were conducted for each miRNA with respect ever-development of metastasis. Multiple survival analyses were done, using the Cox proportional hazards model, to evaluate interactions between miRNA expression, metastasis, and OS. A total of 22 miRNAs (3 upregulated and 19 downregulated) were differentially expressed between patients with vs. without metastatic UM. These 22 miRNAs could be grouped into four clusters based on similarities in expression patterns. Of the 22 miRNAs differentially expressed with respect to metastasis, 21 were significantly associated with OS. The expression of multiple miRNAs was significantly associated with metastasis and overall survival in patients with UM. Further investigation of these miRNAs as biomarkers and/or therapeutic targets is warranted in the push to improve outcomes for patients with metastatic UM.
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Project description:PurposeThe long-term survival of uveal melanoma patients in the US is not known. We compared long-term survival estimates using relative survival, excess absolute risk (EAR), Kaplan-Meier (KM), and competing risk analyses.SettingPopulation based cohort study.Study populationPooled databases from Surveillance, Epidemiology, and End Results data (SEER, SEER-9+SEER-13+SEER-18).Main outcome measureOverall Survival (OS), Metastasis Free Survival (MFS) and relative survival, computed directly or estimated via a model fitted to excess mortality.ResultsThere were 10678 cases of uveal melanoma spanning a period of 42 years (1975-2016). The median age at diagnosis was 63 years (range 3-99). Over half the patients were still alive at the end of 2016 (53%, 5625). The KM estimates of MFS were 0.729 (0.719, 0.74), 0.648 (0.633, 0.663), and 0.616 (0.596, 0.636) at 10, 20, and 30 years, respectively. The cumulative probabilities of melanoma metastatic death at 10, 20 and 30 years were 0.241 (0.236, 0.245), 0.289 (0.283, 0.294), and 0.301 (0.295, 0.307). In the first 5 years since diagnosis of uveal melanoma, the proportion of deaths attributable to uveal melanoma were 1.3 with rapid fall after 10 years. Death due to melanoma were rare beyond 20 years. Relative survival (RS) plateaued to ~60% across 20 to 30 years. EAR parametric modeling yielded a survival probability of 57%.ConclusionsRelative survival methods can be used to estimate long term survival of uveal melanoma patients without knowing the exact cause of death. RS and EAR provide more realistic estimates as they compare the survival to that of a normal matched population. Death due to melanoma were rare beyond 20 years with normal life expectancy reached at 25 years after primary therapy.
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