title: Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes.
abstract: Cancer is a genetic disease, but two patients rarely have identical genotypes. Similarly, patients differ in their clinicopathological parameters, but how genotypic and phenotypic heterogeneity are interconnected is not well understood. Here we build statistical models to disentangle the effect of 12 recurrently mutated genes and 4 cytogenetic alterations on gene expression, diagnostic clinical variables and outcome in 124 patients with myelodysplastic syndromes. Overall, one or more genetic lesions correlate with expression levels of ~20% of all genes, explaining 20-65% of observed expression variability. Differential expression patterns vary between mutations and reflect the underlying biology, such as aberrant polycomb repression for ASXL1 and EZH2 mutations or perturbed gene dosage for copy-number changes. In predicting survival, genomic, transcriptomic and diagnostic clinical variables all have utility, with the largest contribution from the transcriptome. Similar observations are made on the TCGA acute myeloid leukaemia cohort, confirming the general trends reported here.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Moritz
authors.initials: M
authors.lastname: Gerstung
authors.affiliation: LLR Molecular Haematology Unit, NDCLS, RDM, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: 1] Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy [2] Departments of Molecular Medicine and Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.affiliation: Department of Hematology, Oncology, and Palliative Care, Marienhospital Düsseldorf, 40479 Düsseldorf, Germany.
authors.forename: Aristoteles
authors.initials: A
authors.lastname: Giagounidis
authors.affiliation: 1] Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy [2] Department of Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy.
authors.forename: Matteo G Della
authors.initials: MG
authors.lastname: Porta
authors.affiliation: Division of Hematology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Jädersten
authors.affiliation: LLR Molecular Haematology Unit, NDCLS, RDM, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Hamid
authors.initials: H
authors.lastname: Dolatshad
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: National Genetics Reference Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK.
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.affiliation: Department of Haematology, Royal Bournemouth Hospital, Bournemouth BH7 7DW, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Killick
authors.affiliation: Division of Hematology, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
authors.affiliation: 1] Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy [2] Departments of Molecular Medicine and Internal Medicine and Medical Therapy, University of Pavia, 27100 Pavia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Elli
authors.initials: E
authors.lastname: Papaemmanuil
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: LLR Molecular Haematology Unit, NDCLS, RDM, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; D012097:Repressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2