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Team Finds Recurrent Fusion in Aggressive Angiosarcomas

NEW YORK (GenomeWeb) – Japanese researchers have identified a recurrent gene fusion in angiosarcoma tumors that seems to coincide with more aggressive forms of the vascular cancer, which tends to manifest itself in skin, breast, and liver tissue.

As it reported in the current issue of Cancer Research, the team did transcriptome sequencing on cell lines derived from cutaneous angiosarcoma tumors — a form of the disease that often shows up first on the scalp in older individuals. The group found the same fusion between NUP160 and SLC43A3 turned up in more than 80 percent of cell line samples and in nine of 25 primary angiosarcoma samples, corresponding to tumors from individuals who were hospitalized especially quickly after their initial diagnoses.

Introducing the NUP160-SLC43A3 fusion — which lops off part of the NUP160 gene — into a human endothelial cell line appeared to prompt angiosarcoma-like gene expression patterns, the researchers found, while transplantation of fusion-containing cells led to tumor formation in mice. On the other hand, knocking down the fusion's expression dialed back growth of the tumor-derived angiosarcoma cells, supporting the notion that it acts as a tumor driver.

"Our results suggest that full-length NUP160 inhibits cell proliferation, and the truncation of NUP160 stimulates it," senior author Hironobu Ihn, a dermatology and plastic surgery researcher at Kumamoto University, and co-authors wrote.

A few recurrent mutations have already been detected in tumors from cutaneous angiosarcomas and angiosarcomas originating in other parts of the body, the researchers noted. But the full set of alterations driving the disease and the functional effects of these changes remain to be seen.

For the new analysis, the team turned to cultured human cutaneous angiosarcoma cell lines produced using tumor samples from individuals with the disease.

Transcriptome sequencing analyses on these cells, done with an Illumina TruSeq sample prep kit and Illumina HiSeq 2000 platform, pointed to more than 200 genes with diminished expression in the cutaneous angiosarcoma samples compared with control human dermal microvascular endothelial cells. Almost 100 more genes had higher-than-usual expression in angiosarcoma.

The researchers' analysis of the transcript sequences turned up new and known point mutations in genes contributing to blood vessel formation and cancer development. More than a dozen potential fusions fell out of their angiosarcoma cell line transcript data, meanwhile, including numerous reads mapping to the NUP160-SLC43A3 fusion.

The team confirmed the presence of this fusion with the help of RT-PCR, using fluorescence in situ hybridization to track its chromosomal effects.

The NUP160-SLC43A3 fusion was present in 244 of 300 angiosarcoma cell lines, the researchers noted, while testing on 25 primary angiosarcoma scalp tumors revealed recurrent NUP160-SLC43A3 fusions in nine of the cases.

While histopathological tumor features were similar regardless of the NUP160-SLC43A3 fusion status of these tumors, the team found that presence of the fusion coincided with more rapid hospitalization.

Whereas individuals without the NUP160-SLC43A3 fusion ended up in the hospital an average of around nine months after their angiosarcoma diagnosis, those with the fusion in their tumors were hospitalized after just under three months, on average.

The team's follow-up experiments in human cell lines and mouse models supported the notion that the NUP160-SLC43A3 fusion may act as a driver in angiosarcoma formation, prompting angiosarcoma-like gene expression profiles in normal human dermal microvascular endothelial cells as well as tumor formation in mice.

This effect appeared to be due to NUP160 truncation in the fusion, the study's authors explained, though more research is needed to tease apart the cancer-causing mechanism. Nevertheless, they noted that "the detection of NUP160-SLC43A3 by RT-PCR or variant assays may be useful for the diagnosis of challenging [angiosarcoma] cases or the evaluation of surgical margins, especially in well-differentiated angiosarcoma."

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