Reviewing the somatic genetics of melanoma: from current to future analytical approaches

Dutton‐Regester, Ken; Hayward, Nicholas K.

doi:10.1111/j.1755-148x.2012.00975.x

Cited by 47 publications

(40 citation statements)

References 85 publications

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“…While activating mutations in BRAF and NRAS occur in melanoma at rates of 41% and 18%, respectively (25), lower mutation frequency or gene amplifications in other signaling molecules, such as RTKs, can also contribute to melanoma pathogenesis (26)(27)(28). UNC1062 was developed as a MERTKselective tyrosine kinase inhibitor ( Figure 5A).…”

Section: A Novel Mertk Tyrosine Kinase Inhibitor Unc1062 Inhibits Mmentioning

confidence: 99%

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

Schlegel¹,

Sambade²,

Sather³

et al. 2013

J. Clin. Invest.

131

132

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Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. IntroductionAlthough early cutaneous melanoma is usually curable with surgery, distant metastatic melanoma is an aggressive cancer with a median overall survival time of less than 1 year. In 2012, over 75,000 new melanoma diagnoses were expected and over 9,000 deaths were projected (1). Advances in the understanding of distinct melanoma subtypes as well as melanoma immunobiology have resulted in 2 FDA-approved therapies for metastatic melanoma in 2011: vemurafenib, an inhibitor of mutant BRAF -an oncogene present in approximately 50% of melanomas -and ipilimumab, a monoclonal antibody that targets CTLA-4 (2-4). Despite these rather impressive developments, the overall clinical benefit is limited to either small subgroups of patients who

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Section: A Novel Mertk Tyrosine Kinase Inhibitor Unc1062 Inhibits Mmentioning

confidence: 99%

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

Schlegel¹,

Sambade²,

Sather³

et al. 2013

J. Clin. Invest.

131

132

View full text Add to dashboard Cite

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“…Once the oncogenic pressure is relieved (by targeted inhibition of the gene or pathway), the transformed phenotype is partially or fully alleviated. Although the mechanism underlying the upregulation of PKCe in melanoma is not yet known, it is probable that it is linked to mutation(s) currently being discovered as part of the effort to map the melanoma genome (Dutton-Regester and Hayward, 2012;Walia et al, 2012). In the case of ATF2, PKCe functions as the addicting signal to maintain nuclear localization of ATF2 and thus prevents its pro-apoptotic function at the mitochondria.…”

Section: Cytoplasmic Accumulation Of Atf2mentioning

confidence: 99%

ATF2 – at the crossroad of nuclear and cytosolic functions

Lau

Ronai

2012

Journal of Cell Science

100

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SummaryAn increasing number of transcription factors have been shown to elicit oncogenic and tumor suppressor activities, depending on the tissue and cell context. Activating transcription factor 2 (ATF2; also known as cAMP-dependent transcription factor ATF-2) has oncogenic activities in melanoma and tumor suppressor activities in non-malignant skin tumors and breast cancer. Recent work has shown that the opposing functions of ATF2 are associated with its subcellular localization. In the nucleus, ATF2 contributes to global transcription and the DNA damage response, in addition to specific transcriptional activities that are related to cell development, proliferation and death. ATF2 can also translocate to the cytosol, primarily following exposure to severe genotoxic stress, where it impairs mitochondrial membrane potential and promotes mitochondrial-based cell death. Notably, phosphorylation of ATF2 by the epsilon isoform of protein kinase C (PKCe) is the master switch that controls its subcellular localization and function. Here, we summarize our current understanding of the regulation and function of ATF2 in both subcellular compartments. This mechanism of control of a non-genetically modified transcription factor represents a novel paradigm for 'oncogene addiction'.

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“…Participants were recruited from either (a) families with a known mutation in the CDKN2A/p16 (or simply, p16 ) tumor suppressor that confers 28–76% lifetime risk to US residents (Begg et al, 2005; Bishop et al, 2002) or (b) other melanoma-prone families in which magnitude of risk is similar (35–70x approximate relative risk; Dutton-Regester & Hayward, 2012; Kefford et al, 1999), but for whom the melanoma risk cannot be attributed to currently known melanoma predisposition genes. Importantly, based on prior genetic testing of family members, these control families were known not to carry a p16 mutation, and thus new participants recruited from these families served as “no-test controls.”…”

Section: Introductionmentioning

confidence: 99%

Genetic test reporting enhances understanding of risk information and acceptance of prevention recommendations compared to family history-based counseling alone

et al. 2015

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It is unknown whether or why genetic test reporting confers benefits in the understanding and management of cancer risk beyond what patients learn from counseling based on family history. A prospective nonexperimental control group study compared participants from melanoma-prone families who underwent CDKN2A/p16 (p16) genetic testing (27 carriers, 38 noncarriers) to participants from equivalently melanoma-prone families known not to carry a deleterious p16 mutation (31 no-test controls). All participants received equivalent counseling concerning elevated lifetime melanoma risk and corresponding recommendations for prevention and screening. Both immediately and one month after counseling, participants receiving a genetic test result reported greater understanding of their risk, decreased derogation of the risk information, and greater personal applicability of prevention recommendations than no-test controls. Decreased derogation of risk information after test reporting predicted further increases in understanding of melanoma risk and applicability of prevention recommendations one month later. Results suggest unique benefits of genetic test reporting in promoting understanding and acceptance of information about hereditary cancer risk and its management.

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Reviewing the somatic genetics of melanoma: from current to future analytical approaches

Cited by 47 publications

References 85 publications

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

MERTK receptor tyrosine kinase is a therapeutic target in melanoma

ATF2 – at the crossroad of nuclear and cytosolic functions

Genetic test reporting enhances understanding of risk information and acceptance of prevention recommendations compared to family history-based counseling alone

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