Tissue-Specific Oncogenic Activity of KRASA146T

Poulin, Emily J.; Bera, Asim K.; Lu, Jia; Lin, Yi; Strasser, Samantha Dale; Paulo, João A.; Huang, Tannie Q.; Morales, Carolina; Yan, Wei; Cook, Joshua; Nowak, Jonathan A.; Brubaker, Douglas K.; Joughin, Brian A.; Johnson, Christian W.; DeStefanis, Rebecca A.; Ghazi, Phaedra C.; Gondi, Sudershan; Wales, Thomas E.; Iacob, Roxana E.; Bogdanova, Lana; Gierut, Jessica J.; Li, Yina; Engen, John R.; Pérez–Mancera, Pedro A.; Braun, Benjamin S.; Gygi, Steven P.; Lauffenburger, Douglas A.; Westover, Kenneth D.; Haigis, Kevin M.

doi:10.1158/2159-8290.cd-18-1220

Cited by 150 publications

(149 citation statements)

References 57 publications

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“…Mutations in codons 146 and 13 were described in non‐ossifying fibromas, 9 in giant cell lesions of the jaws 8 and in dental implant‐associated giant cell lesions of the jaws, 13 which are also giant cell‐rich lesions but not associated with systemic alterations. These pathogenic mutations have already been extensively studied, but their functional effects seem to be context and tissue specific 15,25,26 . The VUS KRAS p.A134T (rs1565884227) and KRAS p.E37K detected in one sample each have been previously reported as somatic in large intestine cancer and chronic myelomonocytic leukemia (COSMIC, https://cancer.sanger.ac.uk/cosmic), respectively.…”

Section: Discussionmentioning

confidence: 99%

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

Guimarães

Gomes

Pereira

et al. 2020

J Oral Pathology Medicine

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Background Brown tumors are giant cell‐rich lesions that result from abnormal bone metabolism in hyperparathyroidism, one of the most common endocrine disorders worldwide. Brown tumors occasionally affect the jaws and, despite well‐known clinical and microscopic features, their molecular pathogenesis remains unclear. We investigated the presence of pathogenic activating mutations in TRPV4, FGFR1, and KRAS in a cohort of brown tumors since these have recently been reported in giant‐cell lesions of the jaws and non‐ossifying fibromas of the bones (FGFR1 and KRAS), which are histologic mimics of brown tumors. Methods We target sequenced 13 brown tumors of the jaws associated with primary or secondary hyperparathyroidism. As mutations in these genes are known to activate the MAPK/ERK signaling pathway, we also assessed the immunostaining of the phosphorylated form of ERK1/2 (pERK1/2) in these lesions. Results KRAS pathogenic mutations were detected in seven cases (p.G12V n = 4, p.G12D n = 1, p.G13D n = 1, p.A146T n = 1). KRAS variants of unknown significance (VUS), p.A134T and p.E37K, were also detected. All samples showed wild‐type sequences for FGFR1 and TRPV4 genes. The activation of the MAPK/ERK signaling pathway was demonstrated by pERK1/2 immunohistochemical positivity of the brown tumors´ mononuclear cells. Conclusion Mutations in KRAS and activation of the MAPK/ERK signaling pathway were detected in brown tumors of hyperparathyroidism of the jaws, expanding the spectrum of giant cell lesions whose molecular pathogenesis involve RAS signaling.

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Section: Discussionmentioning

confidence: 99%

KRAS mutations in brown tumor of the jaws in hyperparathyroidism

Guimarães

Gomes

Pereira

et al. 2020

J Oral Pathology Medicine

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“…Recent in vitro analysis revealed distinct binding preferences for Ras-Raf interactions with BRAF binding being highly selective for KRAS whilst CRAF was critical for HRAS-mediated MAP kinase signaling (25). Mutational-specificity is also important for Ras biology (12,(26)(27)(28)(29), and structural and biochemical features underpinning mutational differences in nucleotide cycling, allosteric regulation and GEF, GAP and effector interactions are now being defined (14,25,28,(30)(31)(32).…”

Section: Oncogenic Rasmentioning

confidence: 99%

The Frequency of Ras Mutations in Cancer

2020

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Ras is frequently mutated in cancer; however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. In order to provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types. These percentages were then applied to current US cancer incidence statistics to estimate the number of new patients each year that have Ras-mutant cancers. We find that ~19% of cancer patients harbor Ras mutations; equivalent to ~3.4 million new cases per year worldwide. We discuss the Ras isoform and mutation-specific trends evident within the datasets that are relevant to current Ras-targeted therapies. Research.

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“…4,[20][21][22] Animal models (mostly murine) are more accurate/realistic than the 2D in vitro models in capturing a patient's situation and are currently the most widely used model for drug and radiotherapy testing at a pre-clinical level. 2,10,14,15,[23][24][25][26][27] However, they are expensive, difficult to reproduce and complex to use. 4,7,21,23,26,28 Additionally, there is evidence that animal models undergo signicant genetic changes that diverge from the evolutionary course observed in human disease, raising concerns about the models' translatability and application for personalised therapies.…”

Section: Introductionmentioning

confidence: 99%