title: Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia.
abstract: Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Koichi
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032; Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Ana C
authors.initials: AC
authors.lastname: da Silva-Almeida
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Gannie
authors.initials: G
authors.lastname: Tzoneva
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032.
authors.forename: Francesco
authors.initials: F
authors.lastname: Abate
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Martin
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Carpenter
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032.
authors.forename: Alex
authors.initials: A
authors.lastname: Penson
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez-Garcia
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Eckert
authors.affiliation: Hematology Service, Hospital Central de Asturias, 33011 Oviedo, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Nicolas
authors.affiliation: Molecular Oncology Laboratory, Instituto Universitario de Oncologia del Principado de Asturias, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain.
authors.forename: Milagros
authors.initials: M
authors.lastname: Balbin
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY 10032.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sulis
authors.affiliation: Department of Hematology-Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Hematology-Oncology, Saitama Children's Medical Center, Saitama 339-8551, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Onco-Hematology Division, Department, Salute della Donna e del Bambino (SDB), University of Padua, 35128 Padua, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Paganin
authors.affiliation: Onco-Hematology Division, Department, Salute della Donna e del Bambino (SDB), University of Padua, 35128 Padua, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205; Department of Pathology, Ohio State University School of Medicine, Columbus, OH 43210; Department of Pediatrics, Ohio State University School of Medicine, Columbus, OH 43210; Children's Oncology Group, Arcadia, CA 91006.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: Department of Biostatistics, University of Florida, Gainesville, FL 32611.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA 94143; Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94115.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; German Cancer Consortium, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Kirschner-Schwabe
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032; Department of Pathology, Columbia University Medical Center, New York, NY 10032 af2196@columbia.edu tp2151@columbia.edu rr2579@cumc.columbia.edu.
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032; Department of Biomedical Informatics, Columbia University, New York, NY 10032; af2196@columbia.edu tp2151@columbia.edu rr2579@cumc.columbia.edu.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032; Department of Pediatrics, Columbia University Medical Center, New York, NY 10032; Department of Pathology, Columbia University Medical Center, New York, NY 10032 af2196@columbia.edu tp2151@columbia.edu rr2579@cumc.columbia.edu.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D060965:Clonal Evolution / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D011905:Genes, ras; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D014750:Vincristine; D008727:Methotrexate
keywords: acute lymphoblastic leukemia; chemotherapy resistance; genome sequencing; relapsed leukemia