Flash Talk & Poster Presentation 30th Lorne Cancer Conference 2018

A novel familial AML syndrome with a distinctive mutational signature and common driver mutations due to germline MBD4 loss (#204)

Edward Chew 1 2 3 4 , Mathijs A Sanders 5 , Christoffer Flensburg 1 2 , Annelieke Zeilemaker 5 , Sarah E Miller 2 , Adil S al Hinai 5 6 , Ashish Bajel 3 4 , Bram Luiken 5 , Melissa Rijken 5 , Tamara Mclennan 7 , Remco M Hoogenboezem 5 , François G Kavelaars 5 , Marnie E Blewitt 1 7 , Eric M Bindels 5 , Warren S Alexander 1 2 , Bob Löwenberg 5 , Andrew W Roberts 1 2 4 5 , Peter J M Valk 5 , Ian J Majewski 1 2
  1. Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia
  2. Division of Cancer and Haematology, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
  3. Department of Clinical Haematology and Bone Marrow Transplantation, Royal Melbourne Hospital, Parkville, Victoria, Australia
  4. Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
  5. Department of Haematology, Erasmus University Medical Center, Rotterdam, The Netherlands
  6. National Genetic Center, Royal Hospital, Ministry of Health, Sultanate of Oman
  7. Division of Molecular Medicine, The Walter & Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

Acute myeloid leukaemias (AMLs) have a low mutational burden compared to other cancers. Familial cases of AML are rare and often have pre-existing myelodysplastic or bone marrow failure syndromes. Base excision repair proteins (BER) like MBD4 have been linked to solid cancers but not haematological malignancies.

 

Three patients, of whom 2 are siblings, with no previous haematological disorders, developed AML at a young age (<35 years old). All patients had complete loss of MBD4 through germline loss of function mutations. The AMLs were characterised by a high somatic mutation rate (~33 fold above a typical AML). More than 95% of somatic mutations were cytosine to thymine (C>T) mutations in the context of a methylated CG dinucleotide (CG>TG mutations).

 

The AMLs had a distinctive mutational signature, akin to an extreme form of Signature 1. Nine cancers out of 10,638 in the TCGA database also had MBD4 mutations. In a uveal melanoma and a glioblastoma multiforme, the wild type MBD4 allele was lost through copy number alterations. These 2 cancers also had a high mutation rate and the same extreme Signature 1 as our AMLs. Whole genome sequencing of individual myeloid progenitor colonies of MBD4+/+ and MBD4-/- mice recapitulated the high mutation rate and Signature 1. This is consistent with constant deamination of methylcytosine (5mC) in cells, resulting in C>T mutations, and is usually repaired by MBD4.

 

Our AMLs had somatic mutations in the same genes, acquired in the same order (biallelic DNMT3A mutations followed by IDH1/2 mutations). We propose that loss of MBD4 impairs repair of C>T mutations, accelerating the clock-like mutational process of Signature 1. In the haematopoietic compartment, acquisition of DNMT3A mutations provides a selective advantage for that clone. Additional mutations in IDH1/2 and other genes due to impaired BER ultimately result in AML. Furthermore, discovery of other cancers with acquired loss of MBD4 and the same distinctive mutational signature suggests a role in other malignancies.