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Title: Whole-exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1
Authors: McPherson, J.R 
Ong, C.-K
Ng, C.C.-Y
Rajasegaran, V
Heng, H.-L
Yu, W.S.-S
Tan, B.K.-T 
Madhukumar, P 
Teo, M.C.-C 
Ngeow, J 
Thike, A.-A
Rozen, S.G 
Tan, P.-H
Lee, A.-G 
Teh, B.-T 
Yap, Y.-S 
Keywords: neurofibromin
amino acid substitution
breast cancer
case report
chromosome 6q
chromosome loss
copy number variation
fluorescence in situ hybridization
gene mutation
heterozygosity loss
high throughput sequencing
human tissue
indel mutation
malignant peripheral nerve sheath tumor
neurofibromatosis type 1
NF1 gene
priority journal
skin tumor
tumor suppressor gene
Issue Date: 2015
Citation: McPherson, J.R, Ong, C.-K, Ng, C.C.-Y, Rajasegaran, V, Heng, H.-L, Yu, W.S.-S, Tan, B.K.-T, Madhukumar, P, Teo, M.C.-C, Ngeow, J, Thike, A.-A, Rozen, S.G, Tan, P.-H, Lee, A.-G, Teh, B.-T, Yap, Y.-S (2015). Whole-exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1. Cancer Medicine 4 (12) : 1871-1878. ScholarBank@NUS Repository.
Abstract: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of multiple neurofibromas, cafe-au-lait spots, and Lisch nodules. Individuals with NF1 are at increased risk of developing various tumors, such as malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, leukemia, glioma, rhabdomyosarcoma, and breast cancer. Here, we describe the exome sequencing of breast cancer, MPNST, and neurofibroma from a patient with NF1. We identified a germline mutation in the NF1 gene which resulted in conversion of leucine to proline at amino acid position 847. In addition, we showed independent somatic NF1 mutations in all the three tumors (frameshift insertion in breast cancer (p.A985fs), missense mutation in MPNST (p.G23R), and inframe deletion in dermal neurofibroma (p.L1876del-Inf)), indicating that a second hit in NF1 resulting in the loss of function could be important for tumor formation. Each tumor had a distinct genomic profile with mutually exclusive mutations in different genes. Copy number analysis revealed multiple copy number alterations in the breast cancer and the MPNST, but not the benign neurofibroma. Germline loss of chromosome 6q22.33, which harbors two potential tumor suppressor genes, PTPRK and LAMA2, was also identified; this may increase tumor predisposition further. In the background of NF1 syndrome, although second-hit NF1 mutation is critical in tumorigenesis, different additional mutations are required to drive the formation of different tumors. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
Source Title: Cancer Medicine
ISSN: 2045-7634
DOI: 10.1002/cam4.551
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