Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: Importance of copy neutral LOH

Garcia-Linares, Carles; Fernández-Rodríguez, Juana; Terribas, Ernest; Mercadé, Jaume; Pros, Eva; Benito, Llúcia; Benavente, Yolanda; Capellà, Gabriel; Ravella, Anna; Blanco, Ignacio; Kehrer‐Sawatzki, Hildegard; Lázaro, Conxi; Serra, Eduard

doi:10.1002/humu.21387

Cited by 73 publications

(62 citation statements)

References 43 publications

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“…The identification of NF1-associated LOH (probably associated with mitotic recombination) in 24 tumours is consistent with the results reported in a recent study of neurofibromas that assessed NF1-associated LOH in this type of tumour. 47 In our study, MLPA analysis succeeded in identifying only a single intragenic deletion in one neurofibroma, indicating that mitotic recombination was the likely mechanism for LOH in the remaining 24 neurofibromas. Our previous studies found significantly higher levels (approximately 70 and 90%, respectively) of NF1-associated LOH in both PNFs and MPNSTs, 17,18 an indication that NF1-LOH may be less prominent in benign neurofibromas than in PNFs and malignant tumours.…”

Section: Discussionmentioning

confidence: 54%

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

et al. 2011

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Neurofibromatosis type-1 (NF1), caused by heterozygous inactivation of the NF1 tumour suppressor gene, is associated with the development of benign and malignant peripheral nerve sheath tumours (MPNSTs). Although numerous germline NF1 mutations have been identified, relatively few somatic NF1 mutations have been described in neurofibromas. Here we have screened 109 cutaneous neurofibromas, excised from 46 unrelated NF1 patients, for somatic NF1 mutations. NF1 mutation screening (involving loss-of-heterozygosity (LOH) analysis, multiplex ligation-dependent probe amplification and DNA sequencing) identified 77 somatic NF1 point mutations, of which 53 were novel. LOH spanning the NF1 gene region was evident in 25 neurofibromas, but in contrast to previous data from MPNSTs, it was absent at the TP53, CDKN2A and RB1 gene loci. Analysis of DNA/RNA from neurofibroma-derived Schwann cell cultures revealed NF1 mutations in four tumours whose presence had been overlooked in the tumour DNA. Bioinformatics analysis suggested that four of seven novel somatic NF1 missense mutations (p.A330T, p.Q519P, p.A776T, p.S1463F) could be of functional/clinical significance. Functional analysis confirmed this prediction for p.S1463F, located within the GTPase-activating protein-related domain, as this mutation resulted in a 150-fold increase in activated GTP-bound Ras. Comparison of the relative frequencies of the different types of somatic NF1 mutation observed with those of their previously reported germline counterparts revealed significant (P¼0.001) differences. Although non-identical somatic mutations involving either the same or adjacent nucleotides were identified in three pairs of tumours from the same patients (Po0.0002), no association was noted between the type of germline and somatic NF1 lesion within the same individual.

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Section: Discussionmentioning

confidence: 54%

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

et al. 2011

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“…LOH of 22q in tumours from patients with germline SMARCB1 mutations does not seem to be mediated by mitotic recombination, a mechanism frequently causing LOH of other tumour suppressor genes (Makishima and Maciejewski 2011; Garcia-Linares et al 2011; Stewart et al 2012). In eight tumours from patients with germline SMARCB1 mutations, LOH of 22q was found to be caused exclusively by whole chromosome loss or large deletions within 22q, but not by mitotic recombination (Hadfield et al 2010a).…”

Section: Introductionmentioning

confidence: 99%

The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis

et al. 2016

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Schwannomatosis is characterized by the predisposition to develop multiple schwannomas and, less commonly, meningiomas. Despite the clinical overlap with neurofibromatosis type 2 (NF2), schwannomatosis is not caused by germline NF2 gene mutations. Instead, germline mutations of either the SMARCB1 or LZTR1 tumour suppressor genes have been identified in 86% of familial and 40% of sporadic schwannomatosis patients. In contrast to patients with rhabdoid tumours, which are due to complete loss-of-function SMARCB1 mutations, individuals with schwannomatosis harbour predominantly hypomorphic SMARCB1 mutations which give rise to the synthesis of mutant proteins with residual function that do not cause rhabdoid tumours. Although biallelic mutations of SMARCB1 or LZTR1 have been detected in the tumours of patients with schwannomatosis, the classical two-hit model of tumorigenesis is insufficient to account for schwannoma growth, since NF2 is also frequently inactivated in these tumours. Consequently, tumorigenesis in schwannomatosis must involve the mutation of at least two different tumour suppressor genes, an occurrence frequently mediated by loss of heterozygosity of large parts of chromosome 22q harbouring not only SMARCB1 and LZTR1 but also NF2. Thus, schwannomatosis is paradigmatic for a tumour predisposition syndrome caused by the concomitant mutational inactivation of two or more tumour suppressor genes. This review provides an overview of current models of tumorigenesis and mutational patterns underlying schwannomatosis that will ultimately help to explain the complex clinical presentation of this rare disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1753-8) contains supplementary material, which is available to authorized users.

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“…In accordance with Knudson's two-hit hypothesis, biallelic NF1 inactivation is required for tumorogenesis [12]. While the "first hit" is a germ-line mutation, the "second hit" is a somatic mutation which might occur in utero or later leading to inactivation of NF1 [13,14]. Recent reports shows that even haploinsufficiency also have functional implications [15].…”

Section: Discussionmentioning

confidence: 73%

Neurofibromatosis with male breast cancer-risk factor or co-incidence? Report of two rare cases

Tandon

Panwar

Garg

et al. 2015

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The genetic link between neurofibromatosis and breast cancer has recently intrigued the researchers and breast practitioners alike. While the association is well established in females, the same cannot be said for the male breast cancer due to paucity of cases. With only two cases reported previously, our knowledge is sparse. We hereby report two cases of male breast cancer with neurofibromatosis.

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Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: Importance of copy neutral LOH

Cited by 73 publications

References 43 publications

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas

The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis

Neurofibromatosis with male breast cancer-risk factor or co-incidence? Report of two rare cases

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