Pinpointing the Mechanisms that Transform MGUS into Myeloma

A molecular study of monoclonal gammopathy of undetermined significance (MGUS) and myeloma has provided new insight into the biology of myeloma, finding that MGUS is highly genetically abnormal at both gene and chromosome levels.

The study, presented by Aneta Mikulasova, MSc, from the Babak Myeloma Group at Masaryk University in Brno, Czech Republic, at the 2015 European Hematology Association Congress, used both whole-exome sequencing and single nucleotide polymorphism (SNP) arrays.

“Malignant transformation of normal to tumor cells is a multistep process followed by sequential aggregation of hits at different molecular levels,” Ms. Mikulasova and co-authors wrote. “Transformation from a symptomless state, MGUS, to MM can be used as a unique model for cancer development studies. To date, there is very little data regarding the mechanisms leading to disease progression at the molecular level.”

To better characterize the premalignant phenotype in MGUS patients (including single nucleotide variants [SNVs], insertion-deletion changes [indels], and copy number alterations [CNAs]), the researchers performed whole-exome sequencing with SNP array analysis, then compared these results with advanced tumor cells.

Overall, 33 and 69 MGUS patients were included in a whole-exome sequencing and SNP array study, respectively.

CNAs and acquired SNVs were detected in 68 percent (47/69) and 100 percent (33/33) of MGUS patients, compared with 100 percent (91/91; p<10-4) and 100 percent (463/463; p<10-4) of MM patients, respectively.

The overall number of both CNAs and SNVs per patient, however, was significantly lower in MGUS than in MM:

  • Median CNAs: 2 (range = 0-15) versus 16 (range = 2-49; p<10-18)
  • Median SNVs: 89 (range = 9-315) versus 123 (range = 1-897; p<10-4)

The authors identified 42 genes that were recurrently mutated in at least two patients, and two non-large protein coding genes (KLHL6 and NPIPL2) were mutated in at least three cases. These are in addition to the seven genes that were significantly mutated in myeloma in a previous study conducted by Ms. Mikulasova and colleagues, including KRAS (n=2), HIST1H1E (n=2) and NRAS, DIS3, EGR1, LTB, PRKD2 (all n=1).

“We did not find any chromosome translocations involving MYC (8q24.21) or the light chain loci IGK (2p12) and IGL (22q11.2),” the authors reported. There were also no mutations in the TP53, ATM, ATR, and ZNFH4 genes that were identified “as unfavorable factors to MM patients’ survival.”

“We described the main genetic events that are already present in this premalignant state,” the authors explained, proving that complex genetic instability is formed before clinical manifestation – first at the gene level, then at the chromosome level.

The findings suggested that the transformation from MGUS to myeloma is not due to a single genetic abnormality; rather, the high degree of genetic abnormality in MGUS raises the possibility that surrounding cells in the bone marrow produce factors that preclude MGUS cells from progressing to symptomatic myeloma.

Before any definite conclusions about the mechanisms of the transformation from MGUS to myeloma can be made, however, these data need to be replicated in larger studies, and in non-tumor cells as well.


Reference

Mikulasova A, Walker BA, Wardell CP, et al. Exome sequencing points to differences in genetic instability level in MGUS compared to MM. Abstract #S476. Presented at the 2015 European Hematology Association; June 13, 2015; Vienna, Austria.

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