Familial leukaemia and lymphoma, the next generation – redefining familial haematological risk through the Australian familial haematological cancer study (AFHCS)

C Hahn1,2,3, A Brown1,2,3, D Hiwase4, A Schreiber5,6, J Feng6, M Babic1,2, N Poplawski7, M Fine7, R D'Andrea2,3,4 and H Scott1,2,3

  1. Genetics & Molecular Pathology, SA Pathology, Adelaide, SA, Australia
  2. Centre for Cancer Biology, SA Pathology & University of South Australia, Adelaide, SA, Australia
  3. School of Pharmacy & Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia
  4. Department of Haematology, SA Pathology, Adelaide, SA, Australia
  5. School of Molecular and Biological Sciences, University of Adelaide, Adelaide, SA, Australia
  6. ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, SA, Australia
  7. SA Clinical Genetics Service, Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia

AFHCS was founded in 2004 at which time only 1 familial haematological malignancy (FHM) gene was known, RUNX1 causing thrombocytopenia and predominantly MDS/AML. Today, there are at least 12 known FHM genes. We have a growing collection of >120 families as well as large numbers of sporadic HM. We have solved several families through our identification of mutations in genes such as GATA2 and PAX5, and characterisation of novel RUNX1, CEBPA and DDX41 families. Interestingly, phenotypic heterogeneity is seen across families with the same gene mutated. An example is our recent identification of a family with lymphoma segregating with a novel mutation in DDX41 (R164W), where most other DDX41 families identified to-date have predominantly MDS/AML. It is also becoming clear that in addition to characterised mutations segregating in FHM, there are other genetic modifiers that may influence phenotype and penetrance. This is observed as phenotypic diversity and incomplete penetrance of phenotypes within and across families with identical mutations in the same FHM gene, and in anticipation with decreasing age of diagnosis in subsequent generations. We will describe our cohort and NGS data on 200 exomes and genomes from 73 families focussing on identification of germline gene defects in familial lymphoid malignancies. Of note, we are seeing mutations in known and novel DNA repair pathway genes. We will also present evidence that germline genetic variants contribute to sporadic HM. Defining the genetic defect is crucial for accurate and effective genetic counselling, but also for aiming at personalised medicine with defects in some DNA repair genes being susceptible to currently available and new drugs.