Journal ArticleDOI
In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low‐grade serous tumours
Nathalie L.G. Sieben,Patricia Macropoulos,Guido M.J.M. Roemen,Sandra M. Kolkman-Uljee,Gert Jan Fleuren,Rifat Houmadi,Tim C. Diss,Bretta Warren,Mudher Al Adnani,Anton F.P.M. de Goeij,Thomas Krausz,Adrienne M. Flanagan +11 more
TLDR
The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK‐MAP‐kinase pathway compared with 12% of high‐grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serious borderline tumoured tumours do not progress to serious carcinomas.Abstract:
Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.read more
Citations
More filters
Journal ArticleDOI
Cancer genes and the pathways they control.
TL;DR: The purposes of this review are to highlight examples of progress in many areas of cancer research, indicate where knowledge is scarce and point out fertile grounds for future investigation.
Journal ArticleDOI
Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer.
TL;DR: The current status of the different approaches and targets that are under evaluation and development for the therapeutic intervention of this key signaling pathway in human disease are summarized.
Journal ArticleDOI
Evaluating cell lines as tumour models by comparison of genomic profiles
TL;DR: The results indicate that the gap between cell lines and tumours can be bridged by genomically informed choices of cell line models for all tumour types.
Journal ArticleDOI
Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—Shifting the paradigm
Robert J. Kurman,Ie Ming Shih +1 more
TL;DR: It now appears that type I and type II ovarian tumors develop independently along different molecular pathways and that both types develop outside the ovary and involve it secondarily, leading to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors.
Journal ArticleDOI
ERK/MAPK signalling pathway and tumorigenesis.
TL;DR: The present review discusses recent studies on Ras and ERK pathway members and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.
References
More filters
Journal ArticleDOI
Mutations of the BRAF gene in human cancer
Helen Davies,Graham R. Bignell,Charles Cox,Philip J. Stephens,Sarah Edkins,S. M. Clegg,Jon W. Teague,Hayley Woffendin,Mathew J. Garnett,William Bottomley,Neil Davis,Ed Dicks,Rebecca Ewing,Yvonne Floyd,Kristian Gray,S. Hall,Rachel Hawes,Jaime Hughes,Vivian Kosmidou,Andrew Menzies,Catherine Mould,Adrian Parker,Claire Stevens,Stephen Watt,Steven Hooper,Rebecca Wilson,Hiran Jayatilake,Barry A. Gusterson,Colin Cooper,Janet Shipley,Darren Hargrave,Kathy Pritchard-Jones,Norman J. Maitland,Georgia Chenevix-Trench,Gregory J. Riggins,Darell D. Bigner,Giuseppe Palmieri,Antonio Cossu,Adrienne M. Flanagan,Andrew G. Nicholson,Judy W. C. Ho,Suet Yi Leung,Siu Tsan Yuen,Barbara L. Weber,Hilliard F. Seigler,Timothy L. Darrow,Hugh Paterson,Richard Marais,Christopher J. Marshall,Richard Wooster,Michael R. Stratton,P. Andrew Futreal +51 more
TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Journal ArticleDOI
High frequency of BRAF mutations in nevi.
Pamela M. Pollock,Ursula Harper,Katherine S. Hansen,Laura M. Yudt,Mitchell S. Stark,Christiane M. Robbins,Tracy Moses,Galen Hostetter,Urs Wagner,John W. Kakareka,Ghadi Salem,Tom Pohida,Peter J. Heenan,Paul H. Duray,Olli Kallioniemi,Nicholas K. Hayward,Jeffrey M. Trent,Paul S. Meltzer +17 more
TL;DR: In this article, the authors evaluated the timing of mutations in BRAF during melanocytic neoplasia and found that mutations resulted in the V599E amino acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi.
Journal Article
High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma.
Edna Teruko Kimura,Marina N. Nikiforova,Zhaowen Zhu,Jeffrey A. Knauf,Yuri E. Nikiforov,James A. Fagin +5 more
TL;DR: It is shown that a somatic mutation of BRAF, V599E, is the most common genetic change in PTCs, and represents a unique paradigm of human tumorigenesis through mutation of three signaling effectors lying in tandem.
Journal ArticleDOI
Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status.
Harith Rajagopalan,Alberto Bardelli,Christoph Lengauer,Kenneth W. Kinzler,Bert Vogelstein,Victor E. Velculescu +5 more
TL;DR: The results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.
Journal Article
BRAF and RAS mutations in human lung cancer and melanoma
Marcia S. Brose,Patricia Volpe,Michael Feldman,Madhu S. Kumar,Irum Rishi,Renee M. Gerrero,Eugene Einhorn,Meenhard Herlyn,John D. Minna,Andrew G. Nicholson,Jack A. Roth,Steven M. Albelda,Helen Davies,Charles Cox,Graham Brignell,Philip J. Stephens,P. Andrew Futreal,Richard Wooster,Michael R. Stratton,Barbara L. Weber +19 more
TL;DR: Three BRAF mutations identified in this study are novel, altering residues important in AKT-mediated BRAF phosphorylation and suggesting that disruption ofAKT-induced BRAF inhibition can play a role in malignant transformation, first report of mutations documenting this interaction in human cancers.
Related Papers (5)
Ovarian Tumorigenesis : A Proposed Model Based on Morphological and Molecular Genetic Analysis
Ie Ming Shih,Robert J. Kurman +1 more
Mutations of the BRAF gene in human cancer
Helen Davies,Graham R. Bignell,Charles Cox,Philip J. Stephens,Sarah Edkins,S. M. Clegg,Jon W. Teague,Hayley Woffendin,Mathew J. Garnett,William Bottomley,Neil Davis,Ed Dicks,Rebecca Ewing,Yvonne Floyd,Kristian Gray,S. Hall,Rachel Hawes,Jaime Hughes,Vivian Kosmidou,Andrew Menzies,Catherine Mould,Adrian Parker,Claire Stevens,Stephen Watt,Steven Hooper,Rebecca Wilson,Hiran Jayatilake,Barry A. Gusterson,Colin Cooper,Janet Shipley,Darren Hargrave,Kathy Pritchard-Jones,Norman J. Maitland,Georgia Chenevix-Trench,Gregory J. Riggins,Darell D. Bigner,Giuseppe Palmieri,Antonio Cossu,Adrienne M. Flanagan,Andrew G. Nicholson,Judy W. C. Ho,Suet Yi Leung,Siu Tsan Yuen,Barbara L. Weber,Hilliard F. Seigler,Timothy L. Darrow,Hugh Paterson,Richard Marais,Christopher J. Marshall,Richard Wooster,Michael R. Stratton,P. Andrew Futreal +51 more