Whole-exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- McPherson, JR; Ong, C-K; Ng, CC-Y; Rajasegaran, V; Heng, H-L; Yu, WS-S; Tan, BK-T; Madhukumar, P; Teo, MC-C; Ngeow, J; Thike, A-A; Rozen, SG; Tan, P-H; Lee, AS-G; Teh, B-T; Yap, Y-S
Published Date
- December 2015
Published In
Volume / Issue
- 4 / 12
Start / End Page
- 1871 - 1878
PubMed ID
- 26432421
Pubmed Central ID
- PMC5123784
Electronic International Standard Serial Number (EISSN)
- 2045-7634
Digital Object Identifier (DOI)
- 10.1002/cam4.551
Language
- eng
Conference Location
- United States