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

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Laycock-van Spyk et al.
mutation, even though most exhibit no other NF1
symptoms. 69 Patients may also carry inactivating
mutations of other genes, with a recent study identifying
that 70–80 per cent of mutations involve
genes in the Ras/MAPK pathway, including one
tyrosine-protein phosphatase non-receptor type 11
(PTPN11), neuroblastoma RAS viral oncogene
homologue (NRAS), and v-Ki-ras2 kirsten rat
sarcoma viral oncogene homologue (KRAS) as well
as NF1 genes. 70 Additional somatic mutations have
also been reported in the casitas B-lineage lymphoma
(CBL) and additional sex combs-like 1
(ASXL1) genes. 71 In most cases, the NF1 gene is
lost either via LOH or by compound heterozygous
microlesions, 72 which lead to a complete loss of
neurofibromin and hyperactive signalling through
the Ras/MAPK pathway. LOH may occur through
1.2–1.4 Mb interstitial deletions mediated by low
copy number repeat (LCR) elements that flank the
NF1 gene. 73 LOH through uniparental interstitial
isodisomy (50–52.7 Mb) of chromosome 17
through double mitotic recombination, in an
as-yet-unknown initiator cell, has also been
reported. 72 The rarity of such events may indicate
the existence of a selective advantage, conferred
upon the NF1 2/2 cells, which might explain the
propensity of NF1 patients to develop leukaemia. 74
Astrocytomas (ACs)
Optic pathway tumours or ACs are found in ≏15
per cent of paediatric NF1 patients, 75 with the
complete loss of neurofibromin evident in
NF1-associated optic gliomas. 76 Approximately 84
per cent of NF1-associated ACs also exhibit LOH
in the NF1 region, with many tumours also exhibiting
LOH of 17p, suggesting the likely role of
TP53 — or other 17p13-located genes — in AC
formation. 77 As with MPNSTs, biallelic somatic
NF1 mutation in ACs is, again, apparently insufficient
to induce transformation.
Phaeochromocytomas (PCs)
PCs are extremely rare tumours, with only one to
six cases observed per million individuals. PCs
develop from neural crest-derived chromaffin cells,
and the tumour cells produce and release catecholamines,
which cause hypertension and flushing.
These are tumours of the adrenal medulla and
are primarily associated with mutations of the
Ret proto oncogene (RET), von Hippel-Lindau
(VHL), succinate dehydrogenase complex, subunit
B (SDHB), succinate dehydrogenase complex,
subunit C (SDHC), and succinate dehydrogenase
complex, subunit D (SDHD) genes, although LOH
in the NF1 region, as well as LOH of other loci on
both 17q and 17p, have been observed. 78,79
Glomus tumours
Glomus tumours are small (,5 mm), benign, but
often very painful tumours that develop specifically
within the highly innervated glomus body located
at the end of each digit. These tumours appear to
develop from a-smooth muscle actin-positive cells
that have undergone biallelic NF1 inactivation,
resulting in increased Ras/MAPK activity. 80 The
somatic NF1 mutations often differ between
glomus tumours, indicating highly specific tumorigenic
events. Brems et al. 80 have suggested that
glomus tumours, although rare, should now be
recognised as an integral component of the NF1
spectrum of disease.
The somatic mutational spectrum
of NF1-associated tumours
A review of all published — and the authors’ many
unpublished — somatic NF1 alterations associated
with NF1 tumours was undertaken to gain a better
appreciation of NF1 tumorigenesis. As of July 2010,
at least 577 different somatic NF1 gene changes had
been reported in different NF1-associated tumours,
with more than half (323/577; 56 per cent) corresponding
to LOH in the NF1 gene region, some
involving much larger regions of chromosome 17
(Table S1). The level of LOH detected also differs
between cutaneous neurofibromas, PNFs and
MPNSTs (40 per cent, 79 per cent and 85 per cent,
respectively; Table 1). Table 2 provides the incidence
of LOH in the other tumour types, where
628 # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 5. NO 6. 623–690 OCTOBER 2011