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Dutton-Regester K.,QIMR Berghofer Medical Research Institute | Gartner J.J.,U.S. National Cancer Institute | Emmanuel R.,Weizmann Institute of Science | Qutob N.,Weizmann Institute of Science | And 14 more authors.
Oncotarget | Year: 2014

The incidence of melanoma continues to rise globally and is increasing at a rate greater than any other cancer. To systematically search for new genes involved in melanomagenesis, we collated exome sequencing data from independent melanoma cohort datasets, including those in the public domain. We identified recurrent mutations that may drive melanoma growth, survival or metastasis, and which may hold promise for the design of novel therapies to treat melanoma. These included a frequent recurrent (i.e. hotspot) mutation in the 5' untranslated region of RPS27 in ~10% of samples. We show that the mutation expands the 5'TOP element, a motif known to regulate the expression of most of the ribosomal protein family, to which RPS27 belongs, and thus might sensitize the mutated transcript to growth-mediated regulation. This finding highlights not only the important role of non-protein coding genetic aberrations in cancer development but also their potential as novel therapeutic targets. © 2008-2014 Impact Journals, LLC.

Dutton-Regester K.,QIMR Berghofer Medical Research Institute | Kakavand H.,Melanoma Institute of Australia formerly the Sydney Melanoma Unit | Aoude L.G.,QIMR Berghofer Medical Research Institute | Stark M.S.,QIMR Berghofer Medical Research Institute | And 23 more authors.
Pigment Cell and Melanoma Research | Year: 2013

Summary: Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients present with metastatic disease without an evident primary site. To determine their likely site of origin, we combined exome sequencing from 33 MUPs to assess the total rate of somatic mutations and degree of UV mutagenesis. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed that the majority of MUPs exhibited high somatic mutation rates, high ratios of C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. These data suggest that a significant proportion of MUPs arise from regressed or unrecognized primary cutaneous melanomas or arise de novo in lymph nodes from nevus cells that have migrated from the skin. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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