The duality of human oncoproteins: drivers of cancer and congenital disorders

Abstract

Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.

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Fig. 1
Fig. 2: Factors that influence the ability of oncoproteins to cause transformation.
Fig. 3: Genetic transmission of oncoproteins.
Fig. 4: The pathways of oncoprotein signalling in congenital disorders.

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Acknowledgements

The authors thank all the scientists who have contributed to this exciting field and apologize to those colleagues they were unable to cite. P.C. is a fellow of the Jane Coffin Childs Memorial Fund for Medical Research. This research was supported by the Thrasher Research Fund Early Career Award programme (to P.C.), the University of California, San Francisco Program for Breakthrough Biomedical Research Independent Postdoctoral Research Fellow (to P.C.) and the NIH/NCI grant R35CA197709-01 (to F.M.).

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P.C. conceived the ideas for this article and structured the manuscript. All authors contributed equally to writing and reviewing the manuscript.

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Correspondence to Pau Castel.

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Competing interests

P.C. is a co-founder and advisory board member of Venthera. F.M. is a consultant for Aduro Biotech, Amgen, Daiichi, Ideaya Biosciences, Kura Oncology, Leidos Biomedical Research, PellePharm, Pfizer, PMV Pharma, Portola Pharmaceuticals and Quanta Therapeutics, has received research grants from Daiichi and Gilead Sciences and is a consultant for and cofounder of BridgeBio Pharma, DNAtrix, Olema Pharmaceuticals, and Quartz.

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Glossary

Allele bias

In the context of clinical genetics, this is when a specific mutation in a gene is far more frequent than expected.

Modifying alleles

Single-nucleotide polymorphisms that can either decrease or exacerbate a clinical phenotype driven by a pathogenic mutation.

Mosaicism

Characterized by the presence of cells with at least two distinct genetic make-ups.

Schimmelpenning–Feuerstein–Mims syndrome

Neuro-oculocutaneous mosaicism characterized by the presence of skin lesions and pigmentation abnormalities, epilepsy, epibulbar dermoids, cloudy cornea, eyelid colobomas and arteriovascular defects, among other manifestations.

Blaschko lines

Skin patterns found in adults that recapitulate the normal cell development during embryogenesis. These can be often appreciated in individuals with genetically driven skin stains.

Field cancerization

The presence of large areas of tissue affected by carcinogenic mutations, which often contribute to malignant transformation. It is generally the result of a genotoxic exposure during a prolonged time and can lead to the presence of low-grade and high-grade tumours.

Achondroplasia

An autosomal dominant syndrome that is the most common form of skeletal dysplasia in humans and is caused by the FGFR3 mutation G380R. Patients exhibit macrocephaly and short limbs.

Acanthosis nigricans

A hyperpigmentation and hyperkeratosis of the skin.

Arteriovenous malformations

Abnormal blood vessels that tangle and allow direct connection between veins and arteries and can cause pain and severe haemorrhage if ruptured.

G protein-coupled receptor-associated GTPases

Gα proteins are bound to Gβγ, forming an inactive trimeric complex that associates with G protein-coupled receptors (GPCRs). On GPCR stimulation, conformational changes in the receptor lead to Gβγ dissociation and Gα GTP loading and activation, resulting in the production of second messengers; for Gαs (encoded by GNAS) adenylate cyclase and production of cAMP, and for Gαq and Gα11 (encoded by GNAQ and GNA11, respectively) phospholipase C, resulting in diacylglycerol and inositol trisphosphate.

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Castel, P., Rauen, K.A. & McCormick, F. The duality of human oncoproteins: drivers of cancer and congenital disorders. Nat Rev Cancer 20, 383–397 (2020). https://doi.org/10.1038/s41568-020-0256-z

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    • , Pedro A. Perez-Mancera
    • , Tannie Q. Huang
    • , Jangkyung Kim
    • , Joaquim Grego-Bessa
    • , Maria del pilar Alzamora
    • , Scott C. Kogan
    • , Amnon Sharir
    • , Susan H. Keefe
    • , Carolina E. Morales
    • , Denny Schanze
    • , Pau Castel
    • , Kentaro Hirose
    • , Guo N. Huang
    • , Martin Zenker
    • , Dean Sheppard
    • , Ophir D. Klein
    • , David A. Tuveson
    • , Benjamin S. Braun
    •  & Kevin Shannon

    JCI Insight (2020)

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