WHOLE EXOME SEQUENCING REVEALS NOVEL CANDIDATE GENES IN FAMILIAL MDS/AML
Author(s): ,
Ana Rio-Machin
Affiliations:
Centre for Haemato-Oncology,Barts Cancer Institute, Queen Mary University of London,London,United Kingdom
,
Shirleny Cardoso
Affiliations:
Centre for Genomics and Child Health,Blizard Institute, Queen Mary University of London,London,United Kingdom
,
Kiran Tawana
Affiliations:
Centre for Haemato-Oncology,Barts Cancer Institute, Queen Mary University of London,London,United Kingdom
,
Jun Wang
Affiliations:
Centre for Molecular Oncology,Barts Cancer Institute, Queen Mary University of London,London,United Kingdom
,
Calude Chelala
Affiliations:
Centre for Molecular Oncology,Barts Cancer Institute, Queen Mary University of London,London,United Kingdom
,
Vincent Plagnol
Affiliations:
UCL Genetics Institute,London,United Kingdom
,
Yvonne Wallis
Affiliations:
Cancer Programme,West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust,Birmingham,United Kingdom
,
Gavin Ryan
Affiliations:
Cancer Programme,West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust,Birmingham,United Kingdom
,
Alicia Ellison
Affiliations:
Centre for Genomics and Child Health,Blizard Institute, Queen Mary University of London,London,United Kingdom
,
Ahad Al Seraihi
Affiliations:
Centre for Haemato-Oncology,Barts Cancer Institute, Queen Mary University of London,London,United Kingdom
,
Amanda Walne
Affiliations:
Centre for Genomics and Child Health,Blizard Institute, Queen Mary University of London,London,United Kingdom
,
Hemanth Tummala
Affiliations:
Centre for Genomics and Child Health,Blizard Institute, Queen Mary University of London,London,United Kingdom
,
Jude Fitzgibbon
Affiliations:
Centre for Haemato-Oncology,Barts Cancer Institute, Queen Mary University of London,London,United Kingdom
,
Inderjeet Dokal
Affiliations:
Centre for Genomics and Child Health,Blizard Institute, Queen Mary University of London,London,United Kingdom
Tom Vulliamy
Affiliations:
Centre for Genomics and Child Health,Blizard Institute, Queen Mary University of London,London,United Kingdom
EHA Library. Rio-Machin A. 06/11/16; 133433; P545
Dr. Ana Rio-Machin
Dr. Ana Rio-Machin
Contributions
Abstract
Abstract: P545

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) are related heterogeneous haematopoietic stem cell clonal disorders characterised by defective haematopoiesis and premature mortality in many patients. The majority of MDS and AML cases are sporadic but there are also rare cases (<5%) where two or more affected individuals are found within the same family (familial MDS/AML). Familial MDS/AML patients represent a high-risk population who require unique follow-up and treatment strategies to achieve cancer risk reduction, prevention and best management. To date, heterozygous germline mutations in 10 disease genes (ACD, ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72, TERC and TERT) have been associated with the inherited predisposition in these families, but explain only 50-60% of cases. 

Aims
To identify new germ-line mutations in families with MDS/AML of unknown aetiology

Methods
Bone marrow or peripheral blood samples were collected from 78 families, where two or more members have been diagnosed with a haematological disease (AML, MDS, aplastic anaemia or thrombocytopenia) but including at least one with MDS or AML.  Each index case of these families was tested for mutation in the 10 known disease genes using deep targeted sequencing. Whole exome sequencing (WES) was performed in families with still unknown aetiology. Exome libraries were prepared using Illumina Nextera reagents and sequenced on the HiSeq2000. Germline variant calling was performed using GATK and all functional variants were selected. We used the following criteria to enrich for genes with pathogenic relevance: (i) recurrent genes (those with mutations in at least two families); (ii) novel variants or genetic lesions, not described in dbSNP137, ExAC, HAPMAP or the 1000 Genomes projects; (iii) functional annotation based on both PolyPhen scores (> 0.850) and the MutationTaster algorithm (disease causing) to assess pathogenicity. 

Results
46 of the 78 families in our cohort (59%) have mutations in 8 of the 10 known loci (ACD, CEBPA, DDX41, GATA2, RUNX1, SRP72, TERC and TERT). In 32 families of unknown aetiology, whole exome sequencing (WES) was performed and a mean of 422 non-synonymous variants were found per sample. The chosen criteria have allowed us to limit the search to the most relevant germline mutations in our cohort, reducing the number of new candidate disease genes to nine with shared nonsynonymous variants: ATP13A4, COL2A1, DNAJC10, GLDC, LRP2, MAN1C1, PDCD4, SEC23B and TFIP11.

Conclusion
We have identified nine new potential candidate disease genes in familial MDS/AML. However, a single unifying candidate gene has not been identified, suggesting genetic heterogeneity. Further studies will establish which of these can be assigned as true ‘familial MDS/AML’ disease genes.

Session topic: Acute myeloid leukemia - Biology 2

Keyword(s): Familial, MDS/AML, Mutation analysis
Abstract: P545

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) are related heterogeneous haematopoietic stem cell clonal disorders characterised by defective haematopoiesis and premature mortality in many patients. The majority of MDS and AML cases are sporadic but there are also rare cases (<5%) where two or more affected individuals are found within the same family (familial MDS/AML). Familial MDS/AML patients represent a high-risk population who require unique follow-up and treatment strategies to achieve cancer risk reduction, prevention and best management. To date, heterozygous germline mutations in 10 disease genes (ACD, ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72, TERC and TERT) have been associated with the inherited predisposition in these families, but explain only 50-60% of cases. 

Aims
To identify new germ-line mutations in families with MDS/AML of unknown aetiology

Methods
Bone marrow or peripheral blood samples were collected from 78 families, where two or more members have been diagnosed with a haematological disease (AML, MDS, aplastic anaemia or thrombocytopenia) but including at least one with MDS or AML.  Each index case of these families was tested for mutation in the 10 known disease genes using deep targeted sequencing. Whole exome sequencing (WES) was performed in families with still unknown aetiology. Exome libraries were prepared using Illumina Nextera reagents and sequenced on the HiSeq2000. Germline variant calling was performed using GATK and all functional variants were selected. We used the following criteria to enrich for genes with pathogenic relevance: (i) recurrent genes (those with mutations in at least two families); (ii) novel variants or genetic lesions, not described in dbSNP137, ExAC, HAPMAP or the 1000 Genomes projects; (iii) functional annotation based on both PolyPhen scores (> 0.850) and the MutationTaster algorithm (disease causing) to assess pathogenicity. 

Results
46 of the 78 families in our cohort (59%) have mutations in 8 of the 10 known loci (ACD, CEBPA, DDX41, GATA2, RUNX1, SRP72, TERC and TERT). In 32 families of unknown aetiology, whole exome sequencing (WES) was performed and a mean of 422 non-synonymous variants were found per sample. The chosen criteria have allowed us to limit the search to the most relevant germline mutations in our cohort, reducing the number of new candidate disease genes to nine with shared nonsynonymous variants: ATP13A4, COL2A1, DNAJC10, GLDC, LRP2, MAN1C1, PDCD4, SEC23B and TFIP11.

Conclusion
We have identified nine new potential candidate disease genes in familial MDS/AML. However, a single unifying candidate gene has not been identified, suggesting genetic heterogeneity. Further studies will establish which of these can be assigned as true ‘familial MDS/AML’ disease genes.

Session topic: Acute myeloid leukemia - Biology 2

Keyword(s): Familial, MDS/AML, Mutation analysis

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