Genomics Inform.  2017 Sep;15(3):87-97. 10.5808/GI.2017.15.3.87.

Chromothripsis in Treatment Resistance in Multiple Myeloma

Affiliations
  • 1Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang 10408, Korea. ksy@ncc.re.kr
  • 2College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea.
  • 3Department of Laboratory Medicine, Center for Diagnostic Oncology, Research Institute and Hospital, National Cancer Center, Goyang 10408, Korea.
  • 4Center for Hematologic Malignancy, National Cancer Center, Goyang 10408, Korea.
  • 5Precision Medicine Branch, Division of Precision Medicine, National Cancer Center, Goyang 10408, Korea.
  • 6Translational Research Branch, Division of Translational Science, National Cancer Center, Goyang 10408, Korea.

Abstract

Multiple myeloma (MM) is a malignant disease caused by an abnormal proliferation of plasma cells, of which the prognostic factors include chromosomal abnormality, β-2 microglobulin, and albumin. Recently, the term chromothripsis has emerged, which is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event. Many studies have shown an association of chromothripsis with the prognosis in several cancers; however, few studies have investigated it in MM. Here, we studied the association between chromothripsis-like patterns and treatment resistance or prognosis. First, we analyzed nine MM cell lines (U266, MM.1S, RPMI8226, KMS-11, KMS-12-BM, KMS-12-PE, KMS-28-BM, KMS-28-PE, and NCI-H929) and bone marrow samples of four patients who were diagnosed with MM by next-generation sequencing-based copy number variation analysis. The frequency of the chromothripsis-like pattern was observed in seven cell lines. We analyzed the treatment-induced chromothripsis-like patterns in KMS-12-BM and KMS-12-PE cells. As a result, breakpoints and chromothripsis-like patterns were increased after drug treatment in the relatively resistant KMS-12-BM. We further analyzed the patients' results according to the therapeutic response, which was divided into sensitive and resistant, as suggested by the International Myeloma Working Group. The chromothripsis-like pattern was more frequently observed in the resistant group. In the sensitive group, the frequency of the chromothripsis-like pattern decreased after treatment, whereas the resistant group showed increased chromothripsis-like patterns after the treatment. These results suggest that the chromothripsis-like pattern is associated with treatment response in MM.

Keyword

chromothripsis; drug resistance; multiple myeloma
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