Melbourne Medical School Collected Works - Research Publications

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Author: Dobrovic, Alexander × Author: McArthur, Grant × Author: Sheppard, Karen × Type: Journal Article ×

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    Whole exome sequencing identifies a recurrent RQCD1 P131L mutation in cutaneous melanoma
    Wong, SQ ; Behren, A ; Mar, VJ ; Woods, K ; Li, J ; Martin, C ; Sheppard, KE ; Wolfe, R ; Kelly, J ; Cebon, J ; Dobrovic, A ; McArthur, GA (Impact Journals, LLC, 2015)
    Melanoma is often caused by mutations due to exposure to ultraviolet radiation. This study reports a recurrent somatic C > T change causing a P131L mutation in the RQCD1 (Required for Cell Differentiation1 Homolog) gene identified through whole exome sequencing of 20 metastatic melanomas. Screening in 715 additional primary melanomas revealed a prevalence of ~4%. This represents the first reported recurrent mutation in a member of the CCR4-NOT complex in cancer. Compared to tumors without the mutation, the P131L mutant positive tumors were associated with increased thickness (p = 0.02), head and neck (p = 0.009) and upper limb (p = 0.03) location, lentigo maligna melanoma subtype (p = 0.02) and BRAF V600K (p = 0.04) but not V600E or NRAS codon 61 mutations. There was no association with nodal disease (p = 0.3). Mutually exclusive mutations of other members of the CCR4-NOT complex were found in ~20% of the TCGA melanoma dataset suggesting the complex may play an important role in melanoma biology. Mutant RQCD1 was predicted to bind strongly to HLA-A0201 and HLA-Cw3 MHC1 complexes. From thirteen patients with mutant RQCD1, an anti-tumor CD8(+) T cell response was observed from a single patient's peripheral blood mononuclear cell population stimulated with mutated peptide compared to wildtype indicating a neoantigen may be formed.
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    Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines
    Young, RJ ; Waldeck, K ; Martin, C ; Foo, JH ; Cameron, DP ; Kirby, L ; Do, H ; Mitchell, C ; Cullinane, C ; Liu, W ; Fox, SB ; Dutton-Regester, K ; Hayward, NK ; Jene, N ; Dobrovic, A ; Pearson, RB ; Christensen, JG ; Randolph, S ; McArthur, GA ; Sheppard, KE (WILEY-BLACKWELL, 2014-07)
    We have investigated the potential for the p16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three-quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma-specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16(INK) (4A) ) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance.