Summary overview

1. The AAT has funded an extended mutational screen in 291 genes currently known to be mutated in MDS, CHIP and AA, in a subset of RACE trial patients in response to treatment. This has extended the current panel of 31 genes (most commonly mutated in these diseases) that has been funded by CRUK to examine for novel abnormal clones longitudinally.
2. This funding will allow this extended screen to be performed on 300 samples, comprising of paired patient samples for the majority, at pre-treatment and 6 months post-treatment.
3. Sequencing data has been generated for 204 samples (mostly consisting of pre-treatment and 6m follow up samples) and results have been produced and summarized here.
4. Sequencing is by batch, and 300 samples will be completed over the remainder of 2020.
5. For the current batch of 204 samples (104 patients), extensive findings show that in addition to the 31 genes previously screened in the CRUK parallel study, a number of other genes in our extended screen panel are associated with candidate mutations.
6. Genes BCR, KMT2D (and possibly KTM2C) and DNMT1 are the most significant of these new candidate markers at this stage, as candidate acquired variants in these genes are seen in five or more patients, at variant allele frequencies (VAF) that are less likely to represent inherited rare variants. Other variants were also seen here in a number of novel genes, but were not seen as frequently when potential inherited variants were discounted, and therefore their significance in disease is not known until more samples are screened.

King’s College Hospital/King’s College London Research - R. Cook, A. Smith, J.C.W. Marsh, G.J. Mufti, April 2020