Cancer risks associated with the germline MITF(E318K) variant

Guhan, Samantha; Artomov, Mykyta; McCormick, Shelley R.; Njauw, Ching Ni; Stratigos, Alexander J.; Shannon, Kristen E.; Ellisen, Leif W.

doi:10.1038/s41598-020-74237-z

Cited by 21 publications

(16 citation statements)

References 20 publications

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“…Interestingly, a knock-down of MITF in B16F10 melanoma cells and overexpression of MITF in YUMM1.1 cells led to increased tumor growth in vivo in mice [72]. Apart from melanoma, studies have connected MITF with a role in multiple cancers, including non-small cell lung cancer, pancreatic cancer and hepatocellular carcinoma [73][74][75]. Most recently, it was demonstrated that a knockdown of MITF in clear cell renal cell carcinoma cells resulted in reduced cell proliferation and an increase in cells in S/G 2 phases, suppressed cell migration and invasion in vitro and tumor formation in vivo; an opposite effect was observed when MITF was overexpressed [44].…”

Section: Discussionmentioning

confidence: 99%

Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor

Sundaramurthi

García-Mulero

Tonelotto

et al. 2022

Cancers

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Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms. A significant (p = 0.0001) dose-dependent reduction in surviving clones of the primary ocular UM cells, Mel270, was observed upon treatment with increasing doses of ACY-1215. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo attenuation of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0001) following 24 h of treatment, and significant apoptosis was triggered in a time- and dose-dependent manner (p < 0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome profiling, the attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329 significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and reduced OMM2.5 cells in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.

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Section: Discussionmentioning

confidence: 99%

Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor

Sundaramurthi

García-Mulero

Tonelotto

et al. 2022

Cancers

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“…This variant was initially linked to RCC in a study of individuals with RCC, and malignant melanoma and functional studies of this variant demonstrated MITF upregulation through loss of a SUMOylation site ( 27 , 28 ). Though subsequent studies have confirmed an association with melanoma ( 29 ), a recent meta-analysis failed to demonstrate a significant association with RCC ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

Yngvadóttir

Andreou

Bassaganyas

et al. 2022

Human Molecular Genetics

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Background Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Methods Whole genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100000 Genomes Project, a nationwide multicentre study, was analysed to identify rare pathogenic or likely pathogenic (P/LP) short variants (SNVs and INDELs) and structural variants in 121 CSGs. Results Among 1336 RCC participants (mean 61.3 years [±12SD], range 13–88 years; 64% male), 85 participants (6.4%; 95% CI [5.1, 7.8]) had one or more P/LP germline variant in a wider range of CSGs than previously recognised. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 ‘hot VUSs’) and were considered to be of potential clinical relevance as further evaluation might result in their reclassification. Most patients with pathogenic variants in well-established RCC-CSGs were aged < 50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants RCC European participants compared to the healthy European controls (P = 0.0019). Conclusions Approximately 6% of patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.

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“…A systematic review was also performed, evaluating the prevalence of the MITF(E318K) variant in multiple cancer cohorts by germline whole-exome sequencing data from the TCGA panel and from several genetically enriched cohorts. Among the 25 cancers tested (including RCC, PC, pheochromocytoma, paraganglioma and breast cancer), uterine carcinosarcoma (OR 9.24; 95 % CI 2.08–37.17; p = 0.024) and melanoma (OR 2.15; 95 % CI 1.03–4.37; p = 0.061) exhibited the strongest associations with the variant [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature

Oliveira

Gongora

Lima

et al. 2021

Hered Cancer Clin Pract

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Background The microphthalmia-associated transcription factor gene (MITF) belongs to the MYC supergene family and plays an important role in melanocytes’ homeostasis. Individuals harboring MITF germline pathogenic variants are at increased risk of developing cancer, most notably melanoma and renal cell carcinoma. Case presentation We describe a cohort of ten individuals who harbor the same MITF c.952G > A (p.Glu 318Lys), or p.E318K, germline pathogenic variant. Six carriers developed at least one malignancy (4 cases of breast cancer; 1 cervical cancer; 1 colon cancer; 1 melanoma; 1 ovarian/fallopian tube cancer). A significant phenotypic heterogeneity was found among these individuals and their relatives. Breast cancer was, overall, the most frequent malignancy observed in this case series, with 13 occurrences of 60 (21.67 %) total cancer cases described among the probands and their relatives. Conclusions Our retrospective analysis data raise the hypothesis of a possible association of the MITF p.E318K pathogenic variant with an increased risk of breast cancer.

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Cancer risks associated with the germline MITF(E318K) variant

Cited by 21 publications

References 20 publications

Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor

Uveal Melanoma Cell Line Proliferation Is Inhibited by Ricolinostat, a Histone Deacetylase Inhibitor

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases

Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature

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