Whole‐exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1

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.

Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1‐associated malignant peripheral nerve sheath tumors

“…Mutations were identified in 4 genes previously implicated in MPNST pathogenesis in both human studies and genetically engineered mouse models ( NF1, TP53, EGFR , and PDGFR‐α [ PDGFRA ]) . Variants also were identified in other genes potentially involved in MPNST pathogenesis ( GNAQ, SLCO1B1, LAMA2, SLC34A2, PTCH1, RB1, KDR, CYP2A6, MYC, FLT4 , and PSMD2 ) . In addition, there were variants identified in genes not previously implicated in MPNST pathogenesis ( TYK2, CYP2D6, ABCB1, CSF1R, MAP3K1, JAK3, GNA11, FLT3, ROS1, APC, HTR2B, DPYD, ATRX, EV12A, CYP2C19, ALK, GNAS, CYP2B6, BRCA1, NOTCH1, DDR2, RAF1, SMARCB1, FLT1 , smoothened, frizzled class receptor [ SMO ], ESR1, ERBB4, CREBBBP , and ABL1 ).…”

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

“…Among these individuals, one 44-year-old woman previously described with the missense mutation c.2540T>C (p.Leu847Pro) had MPNST, BRCA1/2 -negative (MIM: 113705 and 600185 ) breast cancer as well as a high number of cutaneous neurofibromas (>100). 67 In addition, one individual developed a medullary thyroid carcinoma and three first-degree relatives of a Belgian proband with c.2540T>C (p.Leu847Pro) died from malignancies (a metastasized colon adenocarcinoma and two MPNSTs, both deceased before age 26). Taken together, the overall prevalence of malignant neoplasms in the studied group was substantially higher than in the published datasets of the general NF1-affected population (significant at FDR of 0.05 after B-H correction; Tables 3 and S10 ).…”

RASopathy Gene Mutations in Melanoma

“…Studies show that additional mutations are present in these tumors such as second hits in NF1 and TP53 , multiple copy number alterations, and deletion of CDKN2A (Ratner and Miller, 2015). Whole exome sequencing of tumors from NF1 patient with NF1 L847P revealed that each of the lesions (dermal neurofibromas, breast cancer, MPNST) harbored another mutation in NF1 ; the breast cancer and MPNST presented with additional mutations unique for each tumor (McPherson et al, 2015). …”