Copy Number Gains of DNA Repair Genes Along with TP53 Deletion May Result in Poor Response to Treatment in Newly Diagnosed Multiple Myeloma

• Published in: Transplantation and cellular therapy 2024-02, Vol.30 (2), p.S371-S371
• Main Authors: Raychaudhuri, Jyotishankar, Vasudevan, Smreti, Singh, Aakanksha, Mani, Samson, Singh, Reema, Agrawal, Narendra, Bhurani, Dinesh, Mehta, Anurag
• Format: Article
• Language: English
• ISSN: 2666-6367; 2666-6367
• DOI: 10.1016/j.jtct.2023.12.519

Risk stratification in multiple myeloma is done by cytogenetics and interphase FISH. Recently, a process named ‘Chromothripsis”, literally meaning “shattering of chromosomes”, first described in chronic lymphocytic leukemia, has been shown to be a predictor of “high risk disease’ in newly diagnosed myeloma1. We studied the structural variants in Multiple Myeloma patients with next generation sequencing of the whole genome to decipher the Copy Number Variants as an indicator of chromothripsis. DNA was isolated from CD138+ plasma cells from bone marrow, and library preparation using 20 ng of DNA was done with the Ion AmpiSeq V3 kit and quality checked on Agilent TapeStation. Following automated template preparation and chip loading (Ion Chef System, Ion 520/Ion 530 chip), semiconductor-based sequencing was carried out on the Ion GeneStudio S5 system. Copy number variations (CNVs) were detected in nine patients out of seventeen samples that could be processed. Seven of them were newly diagnosed myeloma (NDMM). Two were relapsed disease. Eight patients had no CNVs. Six patients were detected to have TP53 deletions. Of the CNVs detected three patients had gain of FANC1 and TP53 deletion simultaneously. Two of these three had progressive disease through treatment. (Table 1). Loss of tumor suppressor function and gain of DNA repair abilities, possibly through chromothripsis, may cooperate to create treatment resistant high-risk disease in multiple myeloma. In view of previous reports of involvement of DNA repair pathway genes in multiple myeloma2, the presence of copy number gains in FANC1 in the background of TP53 deletion is interesting. In response to genotoxic insults, ubiquitinated FANCD2 and FANCI are necessary for nucleolytic incisions to unhook the interstrand-crosslinks (ICLs) and for the insertion of nucleotides opposite the unhooked crosslinks3. Thus, more efficient DNA repair mechanisms may help the myeloma cells survive the treatment by genotoxic agents. Here we present early interim data of our work which may stimulate further interest in the subject. More work is needed to find if there is any evolution of these findings between stable and progressive disease, as has been suggested by a few studies 4.