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J.R. Jones et al.
at relapse, with 5% (3 of 56) of patients losing KRAS mutations and 4% (2 of 56) losing NRAS (Figure 1B). The most commonly mutated pathway was the RAS-MAPK pathway, with mutations of one or more of NRAS, KRAS, BRAF, NF1, and EGFR being seen in 57% (33 of 56) of patients at some point during the disease course. Loss of one or more of these mutations was noted in 9% (5 of 56) of patients at relapse while new mutations were seen in 13% (7 of 56). The majority of these new mutations were clonal (CCF>80%) and all had a CCF >20% (range, 0.29- 1) (Online Supplementary Figure S3). The results of these mutational studies are consistent with there being impor- tant changes in subclonal structure at relapse, rather than the simple accumulation of new mutations. The profile of mutations at presentation and relapse in patients who
received lenalidomide or thalidomide induction was well matched (Online Supplementary Table S2).
Acquired structural change is a frequent feature of relapse
We interrogated regions of recurrent CNA that are known to be associated with prognosis: 1p32.3 (FAF1/CDKN2C), 1p12 (FAM46C), 13 (RB1), 14q (TRAF3), and 17p (TP53). Copy number loss of ≥1 of these regions was seen in 63% (35 of 56) of patients at presentation and 59% (33 of 56) at relapse (Online Supplementary Figure S4). There was an evident change in the profile at relapse, with regions of loss seen at presentation returning to a diploid status in 9% (5 of 56) of patients while new losses were seen in 13% (7 of 56). Once again, these features are con-
D
E
A
BC
Figure 3. Number of mutational clus- ters at presentation and relapse. (A) For all 56 patients, the number of mutational clusters was similar at presentation and relapse. The same pattern was seen irrespective of main- tenance strategy (B and C) or depth of response (D and E). This suggests that a change in clonal number is not a major factor in disease progression.
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haematologica | 2019; 104(7)