Annals of Diagnostic Paediatric Pathology

Annals of Diagnostic Paediatric Pathology 2004, 8(3-4):
© Copyright by Polish Paediatric Pathology Society
Genetics and biology of neuroblastoma – an overview
Peter F. Ambros 1 , Ruth Ladenstein 2 , Helmut Gadner 1, 2 , Ingeborg M. Ambros 1
Annals of
Diagnostic
Paediatric
Pathology
1
CCRI, Children’s Cancer Research Institute,
St. Anna Children’s Hospital,
A-1090 Vienna, Austria
2
St. Anna Children’s Hospital,
A-1090 Vienna, Austria
Abstract
Neuroblastoma, the most common extra cranial solid tumor in early childhood, is a heterogeneous disease
with different clinical and biological behavior. Unique features are the spontaneous regression and maturation
which both require similar genetic prerequisites and, in the case of maturation, also the presence of the
non-neoplastic Schwann cells. However, over the half of the tumors display an aggressive clinical course.
Besides the stage and age at diagnosis, the MYCN oncogene (amplified versus non-amplified) has gained
fundamental importance for therapy stratification, particularly in patients with localized disease and in infants.
Further prognostic markers associated with an unfavorable outcome are DNA di-tetraploidy, deletion
at chromosomal regions 1p36, 3p and 11q and gain of 17q, besides others. Most of these genetic markers
have been shown to predict outcome in patients with localized disease while their impact in stage 4 patients
is discussed controversially. Recent data indicate that not even MYCN amplification can separate prognostic
subgroups in the latter patient group. However, a rapid BM-clearing seems to be associated with a far more
favorable outcome even in the group of patients with unfavorable genetic features, thus expressing the response
to chemotherapy and possibly providing an excellent prognostic marker. Furthermore, recent gene
expression studies highlighting the whole transcriptome may provide also valuable information on the dignity
of neuroblastic tumors. We can conclude that MYCN amplification still represents an excellent way to
discriminate aggressive from non- or less aggressive tumors especially in patients with localized disease or
infants. However, new biological and genetic information is necessary to be able to reach our final goal
which is patient tailored therapy based on the genetic and biological profile of the tumor.
Key words: genetics, MYCN, oncogene
Genetic hallmarks in neuroblastic tumors
Over the last few years the amplification of the MYCN
oncogene [11, 32] has taken shape as the most important
marker for the assessment of the dignity of neuroblastic tumors.
Amplifications of this oncogene can be observed in approximately
20% of tumors and are often associated with a
deletion at the short arm of chromosome 1, del1p36 [10]. Both
aberrations can be found in both genetic subgroups (Fig. 1)
which are based on the different DNA-content (di-/tetraploid
versus near-triploid or penta-/hexaploid). What up to now is
entirely unclear is why MYCN amplifications and/or aberrations
of the chromosomal region 1p36.3 occur in only about
15% of the near-triploid neuroblastic tumors while the same
aberrations can be found in approx. 56% of the diploid group
(unpublished data). The genetic aberration which is most frequently
detected in neuroblastic tumors is gain of the long
arm of chromosome 17 (in 66-69% of all cases) [9, 20, 39].
The prognostic value of this aberration has however not yet
been completely clarified and was already opposed [36]. Also
other chromosome aberrations like del11q23 [13, 15, 22, 35,
40] and del3p26 [13, 40] have been described frequently.
Whereby, loss of sequences at 11q may indicate a rather promising
genetic marker especially in MYCN non amplified tumors.
However, one has to keep in mind that genetic/biological
studies will only give clear results when the material to be
tested is of good quality and is present in sufficient amount.
Address for correspondence
Assoc. Prof. Dr. Peter F. Ambros
CCRI, Children's Cancer Research Institute, St. Anna Kinderspital
Kinderspitalgasse 6
A-1090 Vienna, Austria
Phone: +43 1 40470 411
Fax: +431 408 7230
E-mail: ambros@ccri.univie.ac.at