KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia.
High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.
Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
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Malinowska-Ozdowy
Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
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Frech
Research Center for Molecular Medicine (CeMM), Vienna, Austria.
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Schönegger
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
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Eckert
Centro Ricerca Tettamanti, University of Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.
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Cazzaniga
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
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Stanulla
Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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zur Stadt
Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
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Mecklenbräuker
Research Center for Molecular Medicine (CeMM), Vienna, Austria.
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Schuster
Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
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Kneidinger
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
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von Stackelberg
Department of Pediatric Hematology-Oncology, IRCCS Bambino Gesù Hospital, Rome, Italy.
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Locatelli
Department of Pediatrics, Medical University of Schleswig Holstein, Kiel, Germany.
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Schrappe
Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Horstmann
St. Anna Kinderspital, Medical University Vienna, Vienna, Austria.
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Attarbaschi
Research Center for Molecular Medicine (CeMM), Vienna, Austria.
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0000000160913088
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Bock
St. Anna Kinderspital, Medical University Vienna, Vienna, Austria.
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Mann
1] Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria [2] St. Anna Kinderspital, Medical University Vienna, Vienna, Austria.
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Haas
Children's Cancer Research Institute (CCRI), Leukemia Biology Group, Vienna, Austria.
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Panzer-Grümayer
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D050882:CREB-Binding Protein / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D060965:Clonal Evolution; D004171:Diploidy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins