Novel β-synuclein Rearrangements in tumor

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Purpose: The synuclein family includes a-, b-, g-synuclein and is predominantly expressed in neurons. a- and b-synuclein is mutated in Parkinson's disease and dementia with Lewy bodies. Recent studies found up-regulation of the synucleins in several tumors including breast cancer, ovarian cancer, meningioma, and melanoma, and the high level of synuclein was associated with poor prognosis and drug resistance. We describe here a novel intragenic rearrangement of b-synuclein in pediatric T-cell acute lymphoblastic leukemia (T-ALL). An additional case of b-synuclein rearrangement was found in a squamous cell carcinoma of the lung by searching the public TCGA database. Methods Morphological evaluation and immunohistochemistry were used for diagnostic purposes. Karyotype analysis, targeted RNA NGS, FISH, and RT-PCR were used to identify the fusion transcript. Results A pediatric T-ALL carried a translocation of chromosomes 5 and 12, resulting in an in-frame fusion between the b-synuclein ( SNCB ) and the ETS variant transcription factor 6 ( ETV6 ), a gene frequently rearranged in acute myeloid leukemia (AML), B-ALL, and T-ALL. Another SNCB rearrangement involved low-density lipoprotein receptor class A domain containing 3 ( LDLRAD3 ) in a lung carcinoma. Both fusions retained the c-terminal of b-synuclein, a region important for protein interaction. Conclusion We describe the first cases of b-synuclein rearrangement in tumors. Since b-synuclein shares extensive similarity in amino acid sequences with a-synuclein and the a-synuclein binds to 14-3-3, an important regulator of apoptosis, we suspect that the rearranged b-synuclein likely contributes to tumorigenesis by deregulating apoptosis. In addition, the rearranged b-synuclein could deregulate the cell cycle, because overexpression of b-synuclein leads to increased cell proliferation.

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