Neurofibromatosis type 1-associated tumours ... - Human Genomics

REVIEW
Laycock-van Spyk et al.
neurofibroma, coupled with aberrant Remak
bundles, could explain how the neurofibroma integrates
into the surrounding tissue, and it is this that
may lead to the surgical difficulties that often lead to
tumour recurrence. Moreover, it has been suggested
that surgical interference may even increase the
recruitment of surrounding cell types, thereby inadvertently
increasing the growth of lesions leading to
the formation of new neurofibromas. 84 Surgical
biopsy is therefore inherently problematic, and novel
therapeutics are urgently required. Clinical and preclinical
trials targeting different components of the
Ras/MAPK signalling pathway and related growth
factor receptors appear to be more promising. It is
likely, however, that treatment with multiple drugs
may be more effective for NF1 tumours. 5
Concluding remarks
Biallelic inactivation of the NF1 gene, resulting in
the complete loss of functional neurofibromin,
initiates the pathogenic process that eventually
results in the formation of nerve sheath tumours.
NF1 gene inactivation may occur through relatively
subtle lesions that affect just a few DNA bases, or
may involve large genomic changes that affect large
chromosomal regions, or even the entire chromosome
17. This review demonstrates that
NF1-associated tumour types display a considerable
degree of variation in terms of the level of LOH
detected, with cutaneous neurofibromas, PNFs and
MPNSTs. MPNSTs manifest increased levels of
deletion-based LOH, whereas cutaneous neurofibromas
appear to be associated with a localised
deletion of the NF1 gene through mitotic recombination
(the situation in PNFs being somewhat
intermediate). In MPNSTs, additional mutations at
different gene loci are almost certainly involved in
the progression of the tumour.
In terms of the molecular mechanisms of mutagenesis,
both methylation-mediated deamination of
5-methylcytosine and slipped mispairing within
polynucleotide tracts appear to be responsible for
the occurrence of mutation hotspots in both the
germline and the soma. For some types of tumour,
there is interplay between the soma and the
germline, in that the location of the germline
mutation can influence the nature, frequency and
location of the subsequent somatic mutation. 85,86
As yet, however, there is no evidence for this
phenomenon in the context of NF1 tumorigenesis.
Although our knowledge of the role of the NF1
gene in tumorigenesis is ever expanding, definitive
markers of malignant transformation remain to be
discovered. Mouse and other animal models, including
zebrafish, 87 have provided new perspectives for
research, with various knockout and mutagenesis
studies potentiating functional studies. It is already
clear that, in order to clarify the role of the
NF1 gene in NF1-associated tumours, we must
improve our understanding of the significance of
the somatic (second-hit) mutations. The brief
assessment of the compilation of somatic NF1
mutations in NF1-associated tumour types reported
here failed to unearth any specific genotypic correlations.
The limited size of the mutation dataset
means that reliable conclusions are hard to draw,
and that larger and better-defined patient groups
will be needed, to allow more reliable comparisons
to be made. Additionally, definitive prognostic
markers should be identified that permit differentiation
between benign neurofibromas that are likely
to progress to malignancy and those that are not.
This review nevertheless emphasises that NF1 is
a highly individual condition that exhibits extreme
somatic mutational heterogeneity both within and
between patients. These are the mutations which
are ultimately responsible for the molecular changes
that can lead to tumour formation. If we can come
to understand how these changes bring about
tumorigenesis, we shall be better placed not only
with respect to the provision of genetic counselling,
but also in terms of exploring new avenues for the
development of new drug-based therapies.
Acknowledgments
We are grateful to all our NF1 patients and their families for
their support. We also thank Laura Thomas and Gill Spurlock
for their help with the compilation of mutation data.
632 # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 5. NO 6. 623–690 OCTOBER 2011