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Human Genomics

, 11:13

First Online: 21 June 2017Received: 14 May 2017Accepted: 02 June 2017DOI: 10.1186-s40246-017-0109-3

Cite this article as: Philpott, C., Tovell, H., Frayling, I.M. et al. Hum Genomics 2017 11: 13. doi:10.1186-s40246-017-0109-3


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.

KeywordsNF1 Sporadic tumours Somatic mutations Cancer Melanoma Lung cancers Glioblastoma Leukaemia Breast cancer Phaeochromocytoma AbbreviationsADCAdenocarcinoma

AMLAcute myeloid leukaemia

AOCSThe Australian Ovarian Cancer Study

CCLECancer Cell Line Encyclopedia

CMMLChronic myelomonocytic leukaemia

CNSCentral nervous system

COSMICCatalogue of Somatic Mutations in Cancer

HGOSCHigh-grade serous ovarian carcinoma

HRHomologous recombination

ICGCInternational Cancer Genome Consortium

JMMLJuvenile myelomonocytic leukaemia

MAPKMitogen-activated protein kinases

MPNSTMalignant peripheral nerve sheath tumour

NF1Neurofibromatosis type 1

NSCLCNon-small cell lung cancer

OSCOvarian serous carcinoma

PI3KPhosphoinositide-3 kinase

RAS-GEFsRAS guanine nucleotide exchange factors

SCLCSmall cell lung cancer

SqCCSquamous cell lung cancer

T-ALLT cell acute lymphoblastic Leukaemia

TCCUrothelial transitional cell carcinoma

TCGAThe Cancer Genome Atlas

Autor: Charlotte Philpott - Hannah Tovell - Ian M. Frayling - David N. Cooper - Meena Upadhyaya


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