Complex IGH rearrangements in multiple myeloma: Frequent detection discrepancies among three different probe sets

Abstract

Primary IGH translocations involving seven recurrent partner loci and oncogenes are present in about 40% of multiple myeloma tumors. Secondary IGH rearrangements, which occur in a smaller fraction of tumors, usually are complex structures, including insertions or translocations that can involve three chromosomes, and often with involvement of MYC. The main approach to detect IGH rearrangements is interphase – but sometimes metaphase – FISH strategies that use a telomeric variable region probe and a centromeric constant region/Eα enhancer or 3′ flanking probe to detect a separation of these two probes, or a fusion of these probes with probes located at nonrandom partner sites in the genome. We analyzed 18 myeloma cell lines for detection discrepancies among Vysis, Cytocell, and in-house IGH probe sets that hybridize with differing sequences in the IGH locus. There were no detection discrepancies for the three telomeric IGH probes, or for unrearranged IGH loci or primary IGH translocations using the centromeric IGH probes. However, the majority of complex IGH rearrangements had detection discrepancies among the three centromeric IGH probes.

Comparison of <b><i>IGH </i></b>Profile Signals Using t(4;14) and <b><i>IGH</i></b> Break-Apart Probes by FISH in Multiple Myeloma

“…Nevertheless, fusion signals with the FGFR3-IGH probe were well correlated with FGFR3-IGH rearrangements and with patterns described using the CCND1-IGH probe in MM or in chronic lymphocytic leukemia [Trakhtenbrot et al, 2010;Hwang et al, 2011]. Only 2 translocations implying IGH were masked by the FGFR3-IGH probe, but identified with the IGH breakapart probe, and could be explained by the diversity of IGH breakpoints [Walker et al, 2013;Kim et al, 2014].…”

Recent advances in cytogenetic characterization of multiple myeloma

“…As all but one of the IGH translocations lead to gene overexpression by juxtaposition of a given gene near the IGH promoter or enhancers but do not create a fusion transcript, breakpoints can be quite variable within the IGH gene 43. As such, design of the FISH probe plays an important role in the ability to detect not only common but also rare or atypical rearrangements as demonstrated by Kim et al44 in their comparison of various IGH break apart probes.It is thus important to remain alert to the presence of any atypical signal pattern when analyzing MM samples with an IGH break apart, particularly when using this type of probe as first line testing for the detection of IGH rearrangements. However, the cutoffs for these various signal patterns are typically less than 5%.As for dual color dual fusion probes, the cutoffs for the 1O/1G/2F signal pattern corresponding to a balanced translocation are generally less than 5%.…”

Lifetime Pesticide Use and Monoclonal Gammopathy of Undetermined Significance in a Prospective Cohort of Male Farmers

“…Dawley rats, respectively (Hoellinger et al 1987;Institóris et al 1999). More recently, an in vitro study of cultured peripheral blood mononuclear cells exposed to low levels of permethrin reported structural aberrations and increased DNA damage in IGH and KMT2A genes (Navarrete-Meneses et al 2018), both of which are commonly mutated in malignant plasma cells (Kim et al 2014;Landry et al 2013). Notably, in the present study, we found that the risk of MGUS more than doubled among pesticide applicators with continued use of permethrin over their working lifetime (based on reported historical use from the previous AHS enrollment or follow-up questionnaires in combination with reported recent use within the last 12 months at BEEA enrollment) compared with never users (defined as no reported permethrin use on all AHS and BEEA questionnaires).…”