title: Comparative genetic study of intratumoral heterogenous MYCN amplified neuroblastoma versus aggressive genetic profile neuroblastic tumors.
abstract: Intratumoral heterogeneous MYCN amplification (hetMNA) is an unusual event in neuroblastoma with unascertained biological and clinical implications. Diagnosis is based on the detection of MYCN amplification surrounded by non-amplified tumor cells by fluorescence in situ hybridization (FISH). To better define the genetic features of hetMNA tumors, we studied the Spanish cohort of neuroblastic tumors by FISH and single nucleotide polymorphism arrays. We compared hetMNA tumors with homogeneous MNA (homMNA) and nonMNA tumors with 11q deletion (nonMNA w11q-). Of 1091 primary tumors, 28 were hetMNA by FISH. Intratumoral heterogeneity of 1p, 2p, 11q and 17q was closely associated with hetMNA tumors when analyzing different pieces for each case. For chromosome 2, 16 cases showed 2p intact, 4 focal gain at 2p24.3 and 8 MNA. The lengths of the smallest regions of overlap (SROs) for 2p gains and 1p deletions were between the SRO lengths observed in homMNA and nonMNA w11q- tumors. Co-occurrence of 11q- and +17q was frequently found with the largest SROs for both aberrations. The evidence for and frequency of different genetic subpopulations representing a hallmark of the hetMNA subgroup of NB indicates, on one hand, the presence of a considerable genetic instability with different SRO of either gains and losses compared with those of the other NB groups and highlights and, on the other hand, the need for multiple sampling from distant and macroscopically and microscopically distinct tumor areas. Narrowing down the different SRO for both deletions and gains in NB groups would be crucial to pinpointing the candidate gene(s) and the critical gene dosage with prognostic and therapeutic significance. This complexity of segmental chromosomal aberration patterns reinforces the necessity for a larger cohort study using FISH and pangenomic techniques to develop a suitable therapeutic strategy for these patients.
authors.affiliation: Pathology Department, Medical School, University of Valencia, Medical Research Foundation, INCLIVA, Valencia, Spain.
authors.forename: A P
authors.initials: AP
authors.lastname: Berbegall
authors.affiliation: Pathology Department, Medical School, University of Valencia, Medical Research Foundation, INCLIVA, Valencia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Villamón
authors.affiliation: Pathology Department, Medical School, University of Valencia, Medical Research Foundation, INCLIVA, Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Piqueras
authors.affiliation: Pathology Department, Medical School, University of Valencia, Medical Research Foundation, INCLIVA, Valencia, Spain.
authors.forename: I
authors.initials: I
authors.lastname: Tadeo
authors.affiliation: Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Djos
authors.affiliation: CCRI, Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.|Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fé, Valencia, Spain.
authors.forename: P F
authors.initials: PF
authors.lastname: Ambros
authors.affiliation: Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Martinsson
authors.affiliation: CCRI, Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: I M
authors.initials: IM
authors.lastname: Ambros
authors.affiliation: Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fé, Valencia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Cañete
authors.affiliation: Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fé, Valencia, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Castel
authors.affiliation: Pathology Department, Medical School, University of Valencia, Medical Research Foundation, INCLIVA, Valencia, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Navarro
authors.affiliation: Pathology Department, Medical School, University of Valencia, Medical Research Foundation, INCLIVA, Valencia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Noguera
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D015331:Cohort Studies; D018628:Gene Dosage / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000145:classification / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins