Mutations of the BRAF gene in human cancer

Davies, Helen; Bignell, Graham R.; Cox, Charles E.; Stephens, Philip J.; Edkins, Sarah; Clegg, S.; Teague, Jon W.; Woffendin, Hayley; Garnett, Mathew J.; Bottomley, William; Davis, Neil M.; Dicks, Ed; Ewing, Rebecca; Floyd, Yvonne; Gray, Kristian; Hall, Sarah; Hawes, Rachel; Hughes, Jaime; Kosmidou, Vivian; Menzies, Andrew; Mould, Catherine; Parker, Adrian; Stevens, C; Watt, Stephen; Hooper, Steven; Wilson, Roger H. L.; Jayatilake, Hiran; Gusterson, Barry A.; Cooper, Christopher S.; Shipley, Janet; Hargrave, Darren; Pritchard‐Jones, Kathy; Maitland, Norman J.; Chenevix-Trench, Georgia; Riggins, Gregory J.; Bigner, Darell D.; Palmieri, Giuseppe; Cossu, Antonio; Flanagan, Adrienne M.; Nicholson, Andrew G.; Ho, Judy; Leung, Suet Yi; Yuen, Siu Tsan; Weber, Barbara; Seigler, Hilliard F.; Darrow, Timothy L.; Paterson, Hugh; Marais, Richard; Marshall, Christopher J.; Wooster, Richard; Stratton, Michael R.; Futreal, P. Andrew

doi:10.1038/nature00766

Cited by 9,440 publications

(8,324 citation statements)

References 25 publications

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“…We also included the BRAF V600E mutation 53 , which is a frequent driver mutation in melanoma but is also found to a lower percentage (10.7%) in GI tumors 51 . For the structural design of the 19 long mutated peptides, a respective oncogene mutation was placed in the middle of a 28–35-mer peptide.…”

Section: Resultsmentioning

confidence: 99%

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.

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Section: Resultsmentioning

confidence: 99%

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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“…The four genes with recurrent missense mutations were NEK4, KRT3 , BRAF , and MAP4K1 . Only the BRAF (V600E), MSH3 (K381fs), and RNF43 (G659fs) have been previously reported to be a hotspot mutation in many cancers 25, 26, 27, 28, 29…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

Wolff

Hoffman

Wolff

et al. 2018

Genes Chromosomes & Cancer

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Colorectal cancer (CRC) accounts for about 8% of all new cancer cases diagnosed in the US. We used whole exome sequence data from triplet samples (colon carcinoma, colon adenoma, and normal tissue) from 18 individuals to assess gene mutation rates. Of the 2 204 genes that were mutated, APC, TTN, TP53, KRAS, OBSCN, SOX9, PCDH17, SIGLEC10, MYH6, and BRD9 were consistent with genes being an early driver of carcinogenesis, in that they were mutated in multiple adenomas and multiple carcinomas. Fifty‐two genes were mutated in ≥12.5% of microsatellite stable (MSS) carcinomas but not in any of the adenomas, in line with the profile of a late driver event involved in tumor progression. Thirty‐eight genes were sequenced in a larger independent set of 148 carcinoma/normal tissue pairs to obtain more precise mutation frequencies. Eight of the genes, APC, TP53, ATM, CSMD3, LRP1B, RYR2, BIRC6, and MUC17, contained mutations in >20% of the carcinomas. Interestingly, mutations in four genes in addition to APC that are associated with dysregulation of Wnt signaling, were all classified as early driver events. Most of the genes that are commonly associated with colon cancer, including APC, TP53, and KRAS, were all classified as being early driver genes being mutated in both adenomas and carcinomas. Classifying genes as potential early and late driver events points to candidate genes that may help dissect pathways involved in both tumor initiation and progression.

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“…This is of great relevance in cancers such as PTC in which the V600E mutation is observed in a median of 52% of cases (37%–73%) for studies reporting data on mutation frequency, and melanoma in which BRAF is mutated in 50% to 60% of advanced cases (14, 33–39). In a recent phase II study of selumetinib in advanced melanoma, a mutated BRAF status conferred a more favorable outcome.…”

Section: Discussionmentioning

confidence: 99%

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

Hayes

Lucas

Tanvetyanon

et al. 2012

Clinical Cancer Research

141

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Purpose A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of selumetinib in iodine-refractory papillary thyroid cancer (IRPTC). Experimental Design Patients with advanced IRPTC with or without follicular elements and documented disease progression within the preceding 12 months were eligible to receive selumetinib at a dose of 100 mg twice daily. The primary endpoint was objective response rate using Response Evaluation Criteria in Solid Tumors. Secondary endpoints were safety, overall survival, and progression-free survival (PFS). Tumor genotype including mutations in BRAF, NRAS, and HRAS was assessed. Results Best responses in 32 evaluable patients out of 39 enrolled were 1 partial response (3%), 21 stable disease (54%), and 11 progressive disease (28%). Disease stability maintenance occurred for 16 weeks in 49%, 24 weeks in 36%. Median PFS was 32 weeks. BRAF V600E mutants (12 of 26 evaluated, 46%) had a longer median PFS compared with patients with BRAF wild-type (WT) tumors (33 versus 11 weeks, respectively, HR = 0.6, not significant, P = 0.3). The most common adverse events and grades 3 to 4 toxicities included rash, fatigue, diarrhea, and peripheral edema. Two pulmonary deaths occurred in the study and were judged unlikely to be related to the study drug. Conclusions Selumetinib was well tolerated but the study was negative with regard to the primary outcome. Secondary analyses suggest that future studies of selumetinib and other mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) inhibitors in IRPTC should consider BRAF V600E mutation status in the trial design based on differential trends in outcome.

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Mutations of the BRAF gene in human cancer

Cited by 9,440 publications

References 25 publications

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers

Phase II Efficacy and Pharmacogenomic Study of Selumetinib (AZD6244; ARRY-142886) in Iodine-131 Refractory Papillary Thyroid Carcinoma with or without Follicular Elements

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