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

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REVIEW Laycock-van Spyk et al. Table 3: The spectrum and percentile distribution of somatic NF1 micro-lesions reported in different NF1-associated tumours Tumour type Mutation type Deletion Insertion Indel Nonsense Splice site Missense Truncating Total Dermal neurofibroma 82 (39%) 15 (7%) 2 (1%) 59 (28%) 32 (15%) 21 (10%) 158 (75%) 211 Plexiform neurofibroma 6 (33%) 1 (6%) – 7 (39%) 2 (11%) 2 (11%) 14 (78%) 18 Spinal neurofibroma – – – – 2 (66%) 1 (33%) 0 3 MPNST 7 (70%) 1 (10%) 1 (10%) 1 (10%) – – 10 (100%) 10 GIST/gastric carcinoid 1 (20%) – – 3 (60%) 1 (20%) – 4 (80%) 5 JMML * * * * 1 (100%) * * 1 (100%) 1 Glomus tumour 2 (33%) 1 (17%) – 1 (17%) 2 (33%) – 4 (67%) 6 Overall 98 (39%) 18 (7%) 3 (1%) 72 (28%) 39 (15%) 24 (9%) 191 (75%) 254 * Compound heterozygosity of NF1 mutations in several JMML tumours cases meant it was not possible to distinguish between associated germline and somatic NF1 mutations. alterations found in cutaneous neurofibromas at frequencies of 28 per cent (59/211), 15 per cent (32/ 211) and 10 per cent (21/211), respectively (Table 3). Table 3 does, however, serve to highlight the high proportion of truncating mutations (191/ 254; ≏75 per cent) involved in the somatic inactivation of the NF1 gene in all tumour types, especially cutaneous neurofibromas. An additional comparison between the frequency distributions of somatic microlesions and LOH is made in Table 1. There appears to be a marked difference between cutaneous neurofibromas, PNFs and MPNSTs, with 40 per cent, 79 per cent and 85 per cent, respectively, of somatic mutation events represented by LOH. This may be explained in part by the extent of the molecular rearrangements in each tumour type; MPNSTs, for example, would be predicted to exhibit a greater extent of genetic aberration than a benign dermal neurofibroma. The types of analyses performed, however, will have a direct influence on such conclusions, in that either microlesions or LOH may not be screened for in some studies. In summary, the more severe MPNSTs show a greater degree of genetic abnormality than other tumour types, with LOH constituting a much more frequent event in these tumours. Further comparison within and between the rarer tumour types would not be valid, however, owing to the relative paucity of mutation data currently available for analysis. Mutational mechanisms underlying the known somatic NF1 gene lesions Somatic inactivation of the NF1 gene may result from different mutational mechanisms and may involve intragenic mutations, LOH and epigenetic modification of the promoter region. Among the 254 somatic NF1 mutations listed in Table S2, 72 nonsense mutations were found, of which 36 involved mutations in just 15 codons in different tumours (codons 192, 304, 426, 440, 816, 1241, 1306, 1362, 1513, 1569, 1604, 1748, 1939, 1976 and 2429), with many previously reported in different tumours or different studies. Ten of these 15 different recurrent nonsense mutations involve C . Tor G. A transitions within CpG dinucleotides and are compatible with the endogenous mutational mechanism of methylation-mediated deamination of 5-methylcytosine (5mC). Of these 72 nonsense mutations, 28 have also been reported as germline mutations in NF1 patients (Human Gene Mutation Database [HGMD]), 81 indicating that the same mutational mechanism is operating in both the soma and 630 # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 5. NO 6. 623–690 OCTOBER 2011
Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis REVIEW germline. The importance of this mutational mechanism is evidenced by the finding that 12 of the 15 recurrent somatic nonsense mutations have also been reported independently in the germline (codons 192, 304, 426, 440, 816, 1241, 1306, 1362, 1513, 1569, 1748 and 2429). For the ten of these 15 nonsense mutations that correspond to C . Tor G. Atransitions within CpG dinucleotides, we may infer that the mutated cytosine must be methylated both in the soma and in the germline, thereby explaining the vulnerability of these sites to methylation-mediated deamination in both cell lineages. Among the somatic NF1 mutations listed in Table S2 are 21 different missense mutations. Of these, two (in codons 519 and 776) have been reported more than once in different tumours or different studies, although neither is compatible with methylation-mediated deamination of 5mC. Of the 21 missense mutations, only one (in codon 176) has also been reported in the germline (see HGMD). Since this Asp176Glu mutation has also been reported more than once in NF1-associated tumours, it may well be that this residue is of importance for the function of neurofibromin in both the soma and the germline. Furthermore, this residue is conserved in different species, including Drosophila and Fugu, and has not been identified in 250 unrelated normal individuals. Nonsense mutations are not the only type of NF1 mutation to occur recurrently in the soma. Among the somatic NF1 microdeletions listed in Table S2 are five that have been reported more than once in different tumours (c.1888delG, c.2033delC, c.3058delG, c.4374_4375delCC and c.5731delT) with three microdeletions occurring in mononucleotide tracts (G 4 ,C 7 and T 3 , respectively), suggestive of a model of slipped mispairing at the DNA replication fork. Importantly, c.2033delC has also been reported in the germline (see HGMD), indicating that this tetranucleotide stretch is a hotspot for mutation in both the germline and the soma. A microinsertion (c.1733insT, located within a T 6 tract) has also been found to occur recurrently in the soma but this has not so far been reported in the germline. The reader interested in a detailed comparative analysis of germline and somatic mutations in human TSGs is referred to Ivanov et al. 82 NF1 gene somatic mutations in non-NF1-associated tumours Various studies have identified somatic NF1 gene mutations in non-NF1-associated cancers. Thus, somatic NF1 aberrations have been identified in glioblastoma multiforme (GBM) tumours, lung adenocarcinomas, malignant breast tumours, leukaemia, ovarian serous carcinomas (OSCs) and neuroblastoma. 10 – 12,14 – 16,83 Some of the NF1 gene changes are relatively frequent in these tumours and therefore have the potential to represent specific prognostic and diagnostic markers. For example, 23 per cent of sporadic GBM tumours harbour an inactivating NF1 somatic mutation, and this may enable such GBM tumours to differentiate into the mesenchymal molecular subclass. 13 Similarly, in 22 per cent (9/41) of primary OSCs, an NF1 mutation was detected, six of which exhibited biallelic inactivation. 12 Interestingly, all nine of these OSC samples also contained a TP53 mutation, highlighting the likely involvement of this TSG in OSC pathogenesis. 12 Given the pivotal role that neurofibromin plays in several cell signalling pathways, it is not surprising that its loss will affect distinct molecular subtypes in different cancers. Indeed, the efficacy of any future therapeutic intervention for many tumours will almost certainly hinge upon our ability successfully to identify such molecular subclasses of tumour. Prospects for the development of new treatments/therapies As the complex picture underlying the molecular nature of NF1 tumorigenesis becomes better defined, the treatment regimens available to patients should greatly improve. Although the future is encouraging, the optimal treatment for NF1 tumours currently rests with their surgical resection, in spite of the high chance of recurrent malignancy. Gottfried and colleagues 84 have suggested that the recruitment of supporting cells around the # HENRY STEWART PUBLICATIONS 1479–7364. HUMAN GENOMICS. VOL 5. NO 6. 623–690 OCTOBER 2011 631
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