title: Heterogeneous subgroups in human neuroblastoma for clinically relevant risk stratification.
abstract: Neuroblastoma is a heterogeneous tumor and that may have a favorable or unfavorable prognosis. In Japan, a nation-wide neuroblastoma mass-screening (MS) project assessed 6-month-old infants between 1985 and 2003, and almost all neuroblastomas, including regressing or maturing tumors were thought to be detected in this period. To evaluate the heterogeneity of neuroblastoma subgroups, we analyzed patients with neuroblastoma who had been diagnosed during this period. The clinical courses of 4,209 patients with neuroblastoma, including 1,560 MS detected patients, whose tumors had been diagnosed between 1971 and 1995 were registered. The 2,520 cases registered between 1985 and 1995 were compared to 1,050 cases registered between 1971 and 1980 and analyzed by a multi-gene target model to determine the age distribution of neuroblastoma incidence. We hypothesized that three target genes were responsible for the progression of neuroblastoma: one pair of tumor suppressor gene alleles, one oncogene, and one gene controlling regression/differentiation. This simulation study revealed that the age distribution at initial diagnosis of neuroblastoma was divided into four groups based on post-fertilization age: 20-40, 40-50, 60-90, and 160-200 weeks. Since neuroblatoma in the first group occurred prenatal, post-natal clinical neuroblastoma can be classified into three age groups: 0-6 months, 1-2 years, and 3-4 years. The 0- to 6-month group consisted of mostly benign tumors, and the two older groups had predominantly malignant phenotypes. Our proposed model could explain qualitatively the distribution of neuroblastoma consisting of one subgroup with a favorable prognosis and two subgroups with unfavorable prognosis. For clinically relevant risk stratification, an age cutoff should be considered by the age distribution of these heterogeneous subgroups.
authors: Natural Science Center for Basic Research and Development, Hiroshima University, 1-2-3, Kasumi, Hiroshima 734-8551, Japan. eiso@hiroshima-u.ac.jp
authors: Eiso
authors: E
authors: Hiyama
authors: Hiroaki
authors: H
authors: Yamaoka
authors: Satoshi
authors: S
authors: Kondo
authors: Akihiro
authors: A
authors: Yoneda
authors: Tatsuro
authors: T
authors: Tajiri
authors: Masahiro
authors: M
authors: Fukuzawa
authors: Masahiko
authors: M
authors: Sugiyama
authors: Yutaka
authors: Y
authors: Hayashi
authors: Fumiaki
authors: F
authors: Sasaki
authors: Megu
authors: M
authors: Ohtaki
mesh_terms: D017677:Age Distribution; D002675:Child, Preschool; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007223:Infant; D007564:Japan / Q000453:epidemiology; D008403:Mass Screening / Q000379:methods*; D009010:Monte Carlo Method; D009447:Neuroblastoma / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics; D009857:Oncogenes / Q000235:genetics; D010641:Phenotype; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends
references: Cancer. 2001 Nov 1;92(9):2451-61
references: 11745303
references: Science. 1984 Jun 8;224(4653):1121-4
references: 6719137
references: J Clin Oncol. 2005 Sep 20;23(27):6443-4
references: 16116157
references: Cancer Lett. 2005 Oct 18;228(1-2):257-66
references: 16024170
references: Nat Med. 1995 Mar;1(3):249-55
references: 7585042
references: Jpn J Cancer Res. 1992 Feb;83(2):159-64
references: 1555997
references: Cancer. 2001 Nov 15;92(10):2699-708
references: 11745206
references: Lancet Oncol. 2003 Aug;4(8):472-80
references: 12901961
references: Genes Chromosomes Cancer. 2000 Oct;29(2):89-95
references: 10959087
references: J Pediatr Surg. 1990 Oct;25(10):1095-9
references: 2262866
references: Pediatr Blood Cancer. 2007 Feb;48(2):245-6; author reply 247
references: 16652345
references: Pediatr Surg Int. 2004 Jan;20(1):33-8
references: 14691637
references: Br J Cancer. 1954 Mar;8(1):1-12
references: 13172380
references: Med Pediatr Oncol. 2001 Jan;36(1):67-74
references: 11464909
references: J Clin Oncol. 2005 Aug 1;23 (22):5205-10
references: 16051962
references: N Engl J Med. 2002 Apr 4;346(14):1047-53
references: 11932471
references: Nat Rev Cancer. 2003 Mar;3(3):203-16
references: 12612655
references: J Clin Oncol. 2005 Sep 20;23(27):6459-65
references: 16116153
references: J Clin Oncol. 2000 Mar;18(6):1260-8
references: 10715296
references: J Clin Oncol. 2002 Mar 1;20(5):1209-14
references: 11870162
references: Cancer. 1996 Aug 1;78(3):532-41
references: 8697401
references: Hiroshima J Med Sci. 2005 Mar;54(1):9-20
references: 15847060
references: Eur J Cancer. 1997 Oct;33(12):1932-6
references: 9516827
references: Cancer Res. 1971 Dec;31(12):2098-103
references: 5120301
references: J Natl Cancer Inst. 1978 Jul;61(1):49-52
references: 276637
references: Oncogene. 2005 Nov 24;24(53):7902-12
references: 16103881