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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer
Nature Communications Open Access 13 July 2022
Communications Biology Open Access 08 June 2021
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Adams, D. R. & Eng, C. M. Next-generation sequencing to diagnose suspected genetic disorders. N. Engl. J. Med. 379, 1353–1362 (2018).
Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12, 745–755 (2011).
Erickson, R. P. Somatic gene mutation and human disease other than cancer: an update. Mutat. Res. 705, 96–106 (2010).
Martincorena, I. et al. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015). In this study, ultradeep sequencing of skin eyelids reveals the presence of an elevated number of somatic mutations, including many cancer-associated mutations.
Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).
Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, eaaw0726 (2019).
Haigis, K. M., Cichowski, K. & Elledge, S. J. Tissue-specificity in cancer: the rule, not the exception. Science 363, 1150–1151 (2019).
Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017).
Li, S., Balmain, A. & Counter, C. M. A model for RAS mutation patterns in cancers: finding the sweet spot. Nat. Rev. Cancer 18, 767–777 (2018).
Schneider, G., Schmidt-Supprian, M., Rad, R. & Saur, D. Tissue-specific tumorigenesis: context matters. Nat. Rev. Cancer 17, 239–253 (2017).
Mueller, S. et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554, 62–68 (2018).
Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D. & Rauen, K. A. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am. J. Med. Genet. A 140, 8–16 (2006).
Zhao, L. & Vogt, P. K. Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl Acad. Sci. USA 105, 2652–2657 (2008).
Burke, J. E., Perisic, O., Masson, G. R., Vadas, O. & Williams, R. L. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110α (PIK3CA). Proc. Natl Acad. Sci. USA 109, 15259–15264 (2012).
Hobbs, G. A. et al. Atypical KRASG12R mutant is impaired in PI3K signaling and macropinocytosis in pancreatic cancer. Cancer Discov. 10, 104–123 (2020).
Poulin, E. J. et al. Tissue-specific oncogenic activity of KRASA146T. Cancer Discov. 9, 738–755 (2019).
Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380 (2017).
Iwahara, T. et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14, 439–449 (1997).
Vernersson, E. et al. Characterization of the expression of the ALK receptor tyrosine kinase in mice. Gene Expr. Patterns 6, 448–461 (2006).
Sherr, C. J. Principles of tumor suppression. Cell 116, 235–246 (2004).
Schwartz, R. & Schäffer, A. A. The evolution of tumour phylogenetics: principles and practice. Nat. Rev. Genet. 18, 213–229 (2017).
Merino, M. M., Levayer, R. & Moreno, E. Survival of the fittest: essential roles of cell competition in development, aging, and cancer. Trends Cell Biol. 26, 776–788 (2016).
Bowling, S., Lawlor, K. & Rodríguez, T. A. Cell competition: the winners and losers of fitness selection. Development 146, dev167486 (2019).
Hogan, C. et al. Characterization of the interface between normal and transformed epithelial cells. Nat. Cell Biol. 11, 460–467 (2009).
Nelson, C. M. & Bissell, M. J. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 22, 287–309 (2006).
Brown, S. et al. Correction of aberrant growth preserves tissue homeostasis. Nature 548, 334–337 (2017).
Pineda, C. M. et al. Hair follicle regeneration suppresses Ras-driven oncogenic growth. J. Cell Biol. 218, 3212–3222 (2019).
Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).
Swann, J. B. & Smyth, M. J. Immune surveillance of tumors. J. Clin. Invest. 117, 1137–1146 (2007).
Little, J. B. Radiation carcinogenesis. Carcinogenesis 21, 397–404 (2000).
Loeb, L. A. & Harris, C. C. Advances in chemical carcinogenesis: a historical review and prospective. Cancer Res. 68, 6863–6872 (2008).
Steen, H. B. The origin of oncogenic mutations: where is the primary damage? Carcinogenesis 21, 1773–1776 (2000).
Petljak, M. et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell 176, 1282–1294.e20 (2019).
Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat. Genet. 37, 1038–1040 (2005). This study identifies germline HRAS mutations as the causative factor for Costello syndrome, a RASopathy. The authors show that mutations in codon 12 are frequent in these patients, similar to HRAS mutations found in certain human sporadic tumours.
Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
Goriely, A. & Wilkie, A. O. M. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am. J. Hum. Genet. 90, 175–200 (2012).
Maher, G. J. et al. Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes. Proc. Natl Acad. Sci. USA 113, 2454–2459 (2016).
Maher, G. J. et al. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes. Genome Res. 28, 1779–1790 (2018).
Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335–342 (1994).
Hare, L. M. et al. Heterozygous expression of the oncogenic Pik3caH1047R mutation during murine development results in fatal embryonic and extraembryonic defects. Dev. Biol. 404, 14–26 (2015).
Guerra, C. et al. Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111–120 (2003).
Tuveson, D. A. et al. Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).
Schubbert, S. et al. Germline KRAS mutations cause Noonan syndrome. Nat. Genet. 38, 331–336 (2006).
Rauen, K. A. et al. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. Am. J. Med. Genet. A 152A, 807–814 (2010).
Rodriguez-Laguna, L. et al. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J. Exp. Med. 216, 407–418 (2019).
Jacobs, K. B. et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat. Genet. 44, 651–658 (2012).
Laurie, C. C. et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat. Genet. 44, 642–650 (2012).
Forsberg, L. A. et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat. Genet. 46, 624–628 (2014).
Happle, R. Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J. Am. Acad. Dermatol. 16, 899–906 (1987). In this article, the author hypothesizes the reason for which certain dermatological conditions are mosaicisms driven by mutations that do not follow a Mendelian inheritance pattern.
Groesser, L. et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat. Genet. 44, 783–787 (2012). In this article, oncogenic HRAS and KRAS mutations are identified to be the cause of a syndromic mosaicism that is characterized by the presence of sebaceous nevi.
Bolognia, J. L., Orlow, S. J. & Glick, S. A. Lines of Blaschko. J. Am. Acad. Dermatol. 31, 157–190 (1994).
Hafner, C. et al. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc. Natl Acad. Sci. USA 104, 13450–13454 (2007).
Hafner, C. et al. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. J. Clin. Invest. 116, 2201–2207 (2006).
Hafner, C. et al. Keratinocytic epidermal nevi are associated with mosaic RAS mutations. J. Med. Genet. 49, 249–253 (2012).
Biesecker, L. G. & Spinner, N. B. A genomic view of mosaicism and human disease. Nat. Rev. Genet. 14, 307–320 (2013).
Fernández, L. C., Torres, M. & Real, F. X. Somatic mosaicism: on the road to cancer. Nat. Rev. Cancer 16, 43–55 (2016).
Adams, J. R. et al. Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res. 71, 2706–2717 (2011).
Jackson, E. L. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).
Kirsch, D. G. et al. A spatially and temporally restricted mouse model of soft tissue sarcoma. Nat. Med. 13, 992–997 (2007).
Cavenee, W. K. et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305, 779–784 (1983). This study identifies the acquisition of secondary hits in the RB1 gene in patients with retinoblastoma, confirming the Knudson hypothesis.
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Ayturk, U. M. et al. Somatic activating mutations in GNAQ and GNA11 are associated with congenital hemangioma. Am. J. Hum. Genet. 98, 789–795 (2016).
Shirley, M. D. et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N. Engl. J. Med. 368, 1971–1979 (2013).
Cai, X. et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 8, 1280–1289 (2014).
Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).
Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).
Anglesio, M. S. et al. Cancer-associated mutations in endometriosis without cancer. N. Engl. J. Med. 376, 1835–1848 (2017).
Suda, K. et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 24, 1777–1789 (2018).
Hafner, C., Toll, A. & Real, F. X. HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. N. Engl. J. Med. 365, 1940–1942 (2011). In this case report, the authors describe the presence of FGFR3-mutant mosaicism giving rise to both urothelial cancer and epidermal nevi.
Doucet, M. E., Bloomhardt, H. M., Moroz, K., Lindhurst, M. J. & Biesecker, L. G. Lack of mutation-histopathology correlation in a patient with Proteus syndrome. Am. J. Med. Genet. A 170, 1422–1432 (2016).
Sanchez-Vega, F. et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 173, 321–337.e10 (2018).
Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).
Robertson, S. C., Tynan, J. A. & Donoghue, D. J. RTK mutations and human syndromes when good receptors turn bad. Trends Genet. 16, 265–271 (2000).
Bell, D. W. et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat. Genet. 37, 1315–1316 (2005).
Oxnard, G. R., Nguyen, K.-S. H. & Costa, D. B. Germline mutations in driver oncogenes and inherited lung cancer risk independent of smoking history. J. Natl Cancer Inst. 106, djt361 (2014).
Yamamoto, H. et al. Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. J. Natl Cancer Inst. 106, djt338 (2013).
Janoueix-Lerosey, I. et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455, 967–970 (2008).
Mossé, Y. P. et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455, 930–935 (2008).
Morris, S. et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263, 1281 (1994).
Mulligan, L. M. RET revisited: expanding the oncogenic portfolio. Nat. Rev. Cancer 14, 173–186 (2014).
Chompret, A. et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 126, 318–321 (2004).
Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).
Nishida, T. et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat. Genet. 19, 323–324 (1998).
Farrell, B. & Breeze, A. L. Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting. Biochem. Soc. Trans. 46, 1753–1770 (2018).
Muenke, M. et al. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. Am. J. Hum. Genet. 60, 555–564 (1997).
Tavormina, P. L. et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat. Genet. 9, 321–328 (1995).
Reardon, W. et al. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat. Genet. 8, 98–103 (1994).
Hafner, C. et al. High frequency of FGFR3 mutations in adenoid seborrheic keratoses. J. Invest. Dermatol. 126, 2404–2407 (2006).
Muenke, M. et al. A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat. Genet. 8, 269–274 (1994).
Wilkie, A. O. et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat. Genet. 9, 165–172 (1995).
Simanshu, D. K., Nissley, D. V. & McCormick, F. RAS proteins and their regulators in human disease. Cell 170, 17–33 (2017).
Burd, C. E. et al. Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma. Cancer Discov. 4, 1418–1429 (2014).
Nikolaev, S. I. et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N. Engl. J. Med. 378, 250–261 (2018). In this work, the authors identify the presence of cancer-associated KRAS mutations in arteriovenous malformations of the brain.
Al-Olabi, L. et al. Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J. Clin. Invest. 128, 1496–1508 (2018).
Peacock, J. D. et al. Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. Am. J. Med. Genet. A 167, 1429–1435 (2015).
Hafner, C. & Groesser, L. Mosaic RASopathies. Cell Cycle 12, 43–50 (2013).
Groesser, L. et al. Phacomatosis pigmentokeratotica is caused by a postzygotic HRAS mutation in a multipotent progenitor cell. J. Invest. Dermatol. 133, 1998–2003 (2013).
Levinsohn, J. L. et al. Somatic HRAS p.G12S mutation causes woolly hair and epidermal Nevi. J. Invest. Dermatol. 134, 1149–1152 (2014).
Kinsler, V. A. et al. Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS. J. Invest. Dermatol. 133, 2229–2236 (2013).
Charbel, C. et al. NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi. J. Invest. Dermatol. 134, 1067–1074 (2014).
Lim, Y. H. et al. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Hum. Mol. Genet. 23, 397–407 (2014).
Lim, Y. H. et al. Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multilineage somatic mosaic RASopathy. J. Am. Acad. Dermatol. 75, 420–427 (2016).
Florenzano, P., Gafni, R. I. & Collins, M. T. Tumor-induced osteomalacia. Bone Rep. 7, 90–97 (2017).
Kang, H. et al. Somatic activating mutations in MAP2K1 cause melorheostosis. Nat. Commun. 9, 1–12 (2018).
Tidyman, W. E. & Rauen, K. A. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 19, 230–236 (2009).
Goodwin, A. F. et al. Craniofacial and dental development in Costello syndrome. Am. J. Med. Genet. A 164A, 1425–1430 (2014).
Gripp, K. W. et al. Costello syndrome: clinical phenotype, genotype, and management guidelines. Am. J. Med. Genet. A 179, 1725–1744 (2019).
Gripp, K. W. Tumor predisposition in Costello syndrome. Am. J. Med. Genet. C. Semin. Med Genet 137C, 72–77 (2005).
Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 29, 465–468 (2001).
Tartaglia, M. et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat. Genet. 39, 75–79 (2007).
Aoki, Y. et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 93, 173–180 (2013).
Razzaque, M. A. et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat. Genet. 39, 1013–1017 (2007).
Berger, A. H. et al. Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene 33, 4418–4423 (2014).
Lyons, J. et al. Two G protein oncogenes in human endocrine tumors. Science 249, 655–659 (1990).
O’Hayre, M. et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat. Rev. Cancer 13, 412–424 (2013).
Weinstein, L. S. et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N. Engl. J. Med. 325, 1688–1695 (1991). In this article, GNAS is identified as the causative gene for McCune–Albright syndrome. The mutations in this gene are similar to those in endocrine tumours.
Albright, F., Butler, A. M., Hampton, A. O. & Smith, P. Syndrome characterized by osteitis fibrosa disseminata, areas of pigmentation and endocrine dysfunction, with precocious puberty in females. N. Engl. J. Med. 216, 727–746 (1937).
Song, Z.-J. et al. The genome-wide mutational landscape of pituitary adenomas. Cell Res. 26, 1255–1259 (2016).
Wu, J. et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci. Transl. Med. 3, 92ra66 (2011).
Hu, Q. & Shokat, K. M. Disease-causing mutations in the G protein Gαs subvert the roles of GDP and GTP. Cell 173, 1254–1264.e11 (2018).
Van Raamsdonk, C. D. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue nevi. Nature 457, 599–602 (2009).
Van Raamsdonk, C. D. et al. Mutations in GNA11 in uveal melanoma. N. Engl. J. Med. 363, 2191–2199 (2010).
Klebanov, N. et al. Use of targeted next-generation sequencing to identify activating hot spot mutations in cherry angiomas. JAMA Dermatol. 155, 211–215 (2019).
Bilanges, B., Posor, Y. & Vanhaesebroeck, B. PI3K isoforms in cell signalling and vesicle trafficking. Nat. Rev. Mol. Cell Biol. 20, 515–534 (2019).
Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).
Manning, B. D. & Toker, A. AKT/PKB signaling: navigating the network. Cell 169, 381–405 (2017).
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
Carson, J. D. et al. Effects of oncogenic p110α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. Biochem. J. 409, 519–524 (2008).
Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
Madsen, R. R., Vanhaesebroeck, B. & Semple, R. K. Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol. Med. 24, 856–870 (2018).
Kurek, K. C. et al. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. 90, 1108–1115 (2012). In this work, the authors identify mosaic cancer-associated PIK3CA mutations in patients with CLOVES, a syndrome that is now part of PROS.
Rivière, J.-B. et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44, 934–940 (2012).
Lindhurst, M. J. et al. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat. Genet. 44, 928–933 (2012).
Keppler-Noreuil, K. M. et al. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am. J. Med. Genet. A 164A, 1713–1733 (2014).
Castel, P. et al. Somatic PIK3CA mutations as a driver of sporadic venous malformations. Sci. Transl. Med. 8, 332ra42 (2016).
Castillo, S. D. et al. Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. Sci. Transl. Med. 8, 332ra43 (2016).
Luks, V. L. et al. Lymphatic and other vascular malformative/overgrowth disorders are caused by somatic mutations in PIK3CA. J. Pediatr. 166, 1048–1054.e1–5 (2015).
Orloff, M. S. et al. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am. J. Hum. Genet. 92, 76–80 (2013).
Liaw, D. et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat. Genet. 16, 64–67 (1997).
Angulo, I. et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 342, 866–871 (2013).
Kracker, S. et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. J. Allergy Clin. Immunol. 134, 233–236.e3 (2014).
Carpten, J. D. et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439–444 (2007).
Lindhurst, M. J. et al. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365, 611–619 (2011). Sequencing of samples from a patient with Proteus syndrome reveals the presence of mosaic cancer-associated hotspot mutation AKT1 E17K, elucidating the causative gene in this syndrome.
Hussain, K. et al. An activating mutation of AKT2 and human hypoglycemia. Science 334, 474 (2011).
Khan, S. K. et al. Induced Gnas R201H expression from the endogenous Gnas locus causes fibrous dysplasia by up-regulating Wnt/β-catenin signaling. Proc. Natl Acad. Sci. USA 115, E418–E427 (2018).
Lindhurst, M. J. et al. A mouse model of proteus syndrome. Hum. Mol. Genet. 28, 2920–2936 (2019).
Lieschke, G. J. & Currie, P. D. Animal models of human disease: zebrafish swim into view. Nat. Rev. Genet. 8, 353–367 (2007).
Anastasaki, C., Rauen, K. A. & Patton, E. E. Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish. Dis. Model. Mech. 5, 546–552 (2012).
Hernández-Porras, I. et al. K-RasV14I recapitulates Noonan syndrome in mice. Proc. Natl Acad. Sci. USA 111, 16395–16400 (2014).
Wu, X. et al. MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1 L613V mutation. J. Clin. Invest. 121, 1009–1025 (2011).
Komla-Ebri, D. et al. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J. Clin. Invest. 126, 1871–1884 (2016).
Venot, Q. et al. Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature 558, 540–546 (2018). In this work, the authors describe 19 patients with PROS treated under compassionate use with an inhibitor targeting PI3Kα, which was developed and approved to treat metastatic breast cancer.
Pauli, R. M. Achondroplasia: a comprehensive clinical review. Orphanet J. Rare Dis. 14, 1 (2019).
Wendt, D. J. et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J. Pharmacol. Exp. Ther. 353, 132–149 (2015).
Savarirayan, R. et al. C-type natriuretic peptide analogue therapy in children with achondroplasia. N. Engl. J. Med. 381, 25–35 (2019).
Inoue, S.-I., Morozumi, N., Yoshikiyo, K., Maeda, H. & Aoki, Y. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome. Hum. Mol. Genet. 28, 74–83 (2019).
Javle, M. et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J. Clin. Oncol. 36, 276–282 (2018).
Dombi, E. et al. Activity of selumetinib in neurofibromatosis type 1–related plexiform neurofibromas. N. Engl. J. Med. 375, 2550–2560 (2016). In this study, and in reference 160, the authors report the safety and efficacy profiles of the MEK1/MEK2 inhibitor selumetinib for the treatment of plexiform neurofibromas in patients with neurofibromatosis type 1.
Gross, A. M. et al. Selumetinib in children with inoperable plexiform neurofibromas. N. Engl. J. Med. 382, 1430–1442 (2020).
Rauen, K. A. et al. Proceedings of the fifth international RASopathies symposium: when development and cancer intersect. Am. J. Med. Genet. A 176, 2924–2929 (2018).
Andelfinger, G. et al. Hypertrophic cardiomyopathy in Noonan syndrome treated by MEK-inhibition. J. Am. Coll. Cardiol. 73, 2237–2239 (2019).
Rauen, K. A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 14, 355–369 (2013).
Keppler-Noreuil, K. M. et al. Pharmacodynamic study of miransertib in individuals with Proteus syndrome. Am. J. Hum. Genet. 104, 484–491 (2019).
Leoni, C. et al. First evidence of a therapeutic effect of miransertib in a teenager with Proteus syndrome and ovarian carcinoma. Am. J. Med. Genet. A 179, 1319–1324 (2019).
Rodon, J. & Tabernero, J. Improving the armamentarium of PI3K inhibitors with isoform-selective agents: a new light in the darkness. Cancer Discov. 7, 666–669 (2017).
Grippo, P. J., Nowlin, P. S., Demeure, M. J., Longnecker, D. S. & Sandgren, E. P. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res. 63, 2016–2019 (2003).
Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).
Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).
Braun, B. S. et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl Acad. Sci. USA 101, 597–602 (2004).
Haigis, K. M. et al. Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 40, 600–608 (2008).
Johnson, C. W. et al. Isoform-specific destabilization of the active site reveals a molecular mechanism of intrinsic activation of KRas G13D. Cell Rep. 28, 1538–1550.e7 (2019).
Zhang, Z.-T. et al. Role of Ha- ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20, 1973–1980 (2001).
Schuhmacher, A. J. et al. A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. J. Clin. Invest. 118, 2169–2179 (2008).
Oba, D. et al. Mice with an oncogenic HRAS mutation are resistant to high-fat diet-induced obesity and exhibit impaired hepatic energy homeostasis. EBioMedicine 27, 138–150 (2017).
Li, Q.-F., Decker-Rockefeller, B., Bajaj, A. & Pumiglia, K. Activation of Ras in the vascular endothelium induces brain vascular malformations and hemorrhagic stroke. Cell Rep. 24, 2869–2882 (2018).
Chin, L. et al. Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev. 11, 2822–2834 (1997).
Ackermann, J. et al. Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background. Cancer Res. 65, 4005–4011 (2005).
Li, Q. et al. Hematopoiesis and leukemogenesis in mice expressing oncogenic NrasG12D from the endogenous locus. Blood 117, 2022–2032 (2011).
Wang, Y. et al. Mutant N-RAS protects colorectal cancer cells from stress-induced apoptosis and contributes to cancer development and progression. Cancer Discov. 3, 294–307 (2013).
Takahara, S. et al. New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to β-adrenergic stimulation-induced cardiac fibrosis. EBioMedicine 42, 43–53 (2019).
Huang, J. L.-Y., Urtatiz, O. & Van Raamsdonk, C. D. Oncogenic G protein GNAQ induces uveal melanoma and intravasation in mice. Cancer Res. 75, 3384–3397 (2015).
Moore, A. R. et al. GNA11 Q209L mouse model reveals RasGRP3 as an essential signaling node in uveal melanoma. Cell Rep. 22, 2455–2468 (2018).
Saggio, I. et al. Constitutive expression of GsαR201C in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history. J. Bone Miner. Res. 29, 2357–2368 (2014).
Dankort, D. et al. A new mouse model to explore the initiation, progression, and therapy of BRAF V600E-induced lung tumors. Genes Dev. 21, 379–384 (2007).
Dankort, D. et al. BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat. Genet. 41, 544–552 (2009).
Charles, R.-P., Iezza, G., Amendola, E., Dankort, D. & McMahon, M. Mutationally activated BRAFV600E elicits papillary thyroid cancer in the adult mouse. Cancer Res. 71, 3863–3871 (2011).
Inoue, S.-I. et al. Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice. Hum. Mol. Genet. 26, 4715–4727 (2017).
Collisson, E. A. et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2, 685–693 (2012).
Rad, R. et al. A genetic progression model of BrafV600E-induced intestinal tumorigenesis reveals targets for therapeutic intervention. Cancer Cell 24, 15–29 (2013).
Aoidi, R. et al. Mek1 Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome. Dis. Model. Mech. 11, dmm031278 (2018).
Roy, A. et al. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. eLife 4, e12703 (2015).
Stratikopoulos, E. E. et al. Mouse ER+/PIK3CAH1047R breast cancers caused by exogenous estrogen are heterogeneously dependent on estrogen and undergo BIM-dependent apoptosis with BH3 and PI3K agents. Oncogene 38, 47–59 (2019).
Eser, S. et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23, 406–420 (2013).
Avery, D. T. et al. Germline-activating mutations in PIK3CD compromise B cell development and function. J. Exp. Med. 215, 2073–2095 (2018).
Mancini, M. L., Lien, E. C. & Toker, A. Oncogenic AKT1E17K mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis. Oncotarget 7, 17301–17313 (2016).
Wang, Y. et al. A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. Proc. Natl Acad. Sci. USA 96, 4455–4460 (1999).
Logié, A. et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Hum. Mol. Genet. 14, 1153–1160 (2005).
Ahmad, I. et al. K-Ras and β-catenin mutations cooperate with Fgfr3 mutations in mice to promote tumorigenesis in the skin and lung, but not in the bladder. Dis. Model. Mech. 4, 548–555 (2011).
Sommer, G. et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc. Natl Acad. Sci. USA 100, 6706–6711 (2003).
Ono, S., Saito, T., Terui, K., Yoshida, H. & Enomoto, H. Generation of conditional ALK F1174L mutant mouse models for the study of neuroblastoma pathogenesis. Genesis 57, e23323 (2019).
Berry, T. et al. The ALKF1174L mutation potentiates the oncogenic Activity of MYCN in Neuroblastoma. Cancer Cell 22, 117–130 (2012).
Chiarle, R. et al. NPM-ALK transgenic mice spontaneously develop T-cell lymphomas and plasma cell tumors. Blood 101, 1919–1927 (2003).
Soda, M. et al. A mouse model for EML4-ALK-positive lung cancer. Proc. Natl Acad. Sci. USA 105, 19893–19897 (2008).
Politi, K. et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev. 20, 1496–1510 (2006).
Rous, P. A transmissible avian neoplasm. (Sarcoma of the common fowl.). J. Exp. Med. 12, 696–705 (1910).
Halberstaedter, L., Doljanski, L. & Tenenbaum, E. Experiments on the cancerization of cells in vitro by means of Rous sarcoma agent. Br. J. Exp. Pathol. 22, 179–187 (1941).
Harvey, J. J. An unidentified virus which causes the rapid production of tumours in mice. Nature 204, 1104–1105 (1964).
Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).
Santos, E., Tronick, S. R., Aaronson, S. A., Pulciani, S. & Barbacid, M. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature 298, 343–347 (1982).
Parada, L. F., Tabin, C. J., Shih, C. & Weinberg, R. A. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297, 474–478 (1982).
Der, C. J., Krontiris, T. G. & Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc. Natl Acad. Sci. USA 79, 3637–3640 (1982).
Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. & Roberts, T. M. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239–242 (1985).
Gurumurthy, C. B. & Lloyd, K. C. K. Generating mouse models for biomedical research: technological advances. Dis. Model. Mech. 12, dmm029462 (2019).
Kersten, K., de Visser, K. E., van Miltenburg, M. H. & Jonkers, J. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol. Med. 9, 137–153 (2017).
Heyer, J., Kwong, L. N., Lowe, S. W. & Chin, L. Non-germline genetically engineered mouse models for translational cancer research. Nat. Rev. Cancer 10, 470–480 (2010).
Zambrowicz, B. P. et al. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells. Proc. Natl Acad. Sci. USA 94, 3789–3794 (1997).
Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).
Kinross, K. M. et al. An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Invest. 122, 553–557 (2012).
McLellan, M. A., Rosenthal, N. A. & Pinto, A. R. Cre-loxP-mediated recombination: general principles and experimental considerations. Curr. Protoc. Mouse Biol. 7, 1–12 (2017).
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.).
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.
Peer review information
Nature Reviews Cancer thanks S. Chanock, K. Haigis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Online Mendelian Inheritance in Man (OMIM): https://www.omim.org
- 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.
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.
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.
About this article
Cite this article
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
This article is cited by
Nature Cardiovascular Research (2022)
Qualitative differences in disease-associated MEK mutants reveal molecular signatures and aberrant signaling-crosstalk in cancer
Nature Communications (2022)
Communications Biology (2021)
Nature Reviews Drug Discovery (2021)
Nature Cancer (2021)