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CURATOR
A pinboard by
Ken Dutton-Regester

Research Officer, QIMR Berghofer Medical Research Institute

PINBOARD SUMMARY

To identify the genetic causes driving the growth of melanoma to improve existing treatments.

Melanoma is a cancer of melanocytes, the cells responsible for the tanning effect when your skin gets exposed to the sun. While melanoma has one of the highest cure rates of any cancer when detected early, once it spreads (or metastasizes) throughout the body your chances of survival dramatically decrease. Fortunately, our treatment options for metastatic melanoma have rapidly expanded in the last 5 years (6 drug approvals); however, drug-resistance, patients not responding to treatment, and unintended side effects are all issues that still need to be resolved before we can reach ‘a cure’.

As such, a core focus of my research has been to identify the genetic causes of melanoma in order to improve treatment strategies for metastatic disease. My work, in conjunction with national and international collaborators, have helped to identify new drug targets and resolve some of the unknown mechanisms of drug resistance. These findings, have contributed to our understanding of disease and have laid the foundation for improving survival outcomes for patients with metastatic melanoma.

More recently, I have been using genome-wide perturbation technologies (shRNA and CRISPR) to identify genetic dependencies in melanoma. To put that into simple terms, I’m trying to find genes that when turned off will cause cell death in melanoma. Proving that this approach works, we have re-identified existing drug targets for which there are approved therapies for late stage melanoma available (BRAF and MEK inhibitors). We are now following up the next genes on the list to see if we can find new drug targets or new genes that can tell us how melanoma develops.

To find out more about my research: www.linkedin.com/in/kenduttonregester

6 ITEMS PINNED

A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.

Abstract: So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

Pub.: 15 Nov '11, Pinned: 11 Jul '17

Whole-genome landscapes of major melanoma subtypes.

Abstract: Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-coding mutations in cutaneous melanoma resolved novel signatures of mutagenesis attributable to ultraviolet radiation. However, acral and mucosal melanomas were dominated by structural changes and mutation signatures of unknown aetiology, not previously identified in melanoma. The number of genes affected by recurrent mutations disrupting non-coding sequences was similar to that affected by recurrent mutations to coding sequences. Significantly mutated genes included BRAF, CDKN2A, NRAS and TP53 in cutaneous melanoma, BRAF, NRAS and NF1 in acral melanoma and SF3B1 in mucosal melanoma. Mutations affecting the TERT promoter were the most frequent of all; however, neither they nor ATRX mutations, which correlate with alternative telomere lengthening, were associated with greater telomere length. Most melanomas had potentially actionable mutations, most in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways. The whole-genome mutation landscape of melanoma reveals diverse carcinogenic processes across its subtypes, some unrelated to sun exposure, and extends potential involvement of the non-coding genome in its pathogenesis.

Pub.: 04 May '17, Pinned: 11 Jul '17