The NF1 somatic mutational landscape in sporadic human cancers

Abstract

BackgroundNeurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1.Main bodyCapitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context.ConclusionAs neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.

Identification of potential hub genes via bioinformatics analysis combined with experimental verification in colorectal cancer

“…CBioPortal is used to show the correlation between the hub genes and genetic changes. Different types of gene mutations are key reasons for tumor formation 30‐32 …”

Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease

“…On the contrary, as NF1 is a known tumour suppressor within the MAPK pathway, the frameshift mutation we detected would probably cooperate with the putative MAPK1 gain of function mutation to enhance MAPK signalling and cell proliferation. Therefore, the simultaneous presence of multiple mutations in the same pathway would be similar in principle to the genetic landscape of more thoroughly characterized human malignancies, such as melanoma, in which individual cases are known to harbour concurrent deleterious mutations in NF1 as well activating mutations of MAPK‐related oncogenes, such as BRAF or NRAS (Hodis et al , ; Philpott et al , ).…”

Primary renal well‐differentiated neuroendocrine tumour (carcinoid): next‐generation sequencing study of 11 cases

“…Identification of a germline or somatic NF1 aberration can be challenging, as NF1 is one of the largest human genes, and a wide spectrum of mutation types was observed in NF1 . Furthermore, many highly homologous NF1 pseudogene sequences are scattered throughout the human genome, and can often interfere with PCR‐based diagnostic tests (despite the absence of any obvious mutational hotspots or recurrent mutations) . With this knowledge, most of the alterations of NF1 were eliminated as non‐pathogenic after an updated manual filtering process by the use of available databases and the literature …”