Macgregor S, Montgomery GW, Liu JZ et al.Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3. Nat Genet 43:1114-1118

Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Nature Genetics (Impact Factor: 29.35). 11/2011; 43(11):1114-8. DOI: 10.1038/ng.958
Source: PubMed


We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

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    • "We find evidence for allelic stratification between South Asians and Europeans of variants in OCA2, SLC45A2, SLC24A4, TYR, TYRP and other genes involved in melanin pigmentation of skin, hair and eyes [26]–[29]. The differentiation of risk alleles is sufficient to account entirely for the increased pigmentation amongst South Asians, and may explain the low incidence of skin cancers in this population [30], [31]. "
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    ABSTRACT: The genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.
    PLoS ONE 08/2014; 9(8):e102645. DOI:10.1371/journal.pone.0102645 · 3.23 Impact Factor
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    • "It is mapped to the human chromosome 1q21.1516 SETDB1 has been established as an oncogene in human lung cancer, melanoma and kidney tumors.161718 Expression datasets for SETDB1 in cervix squamous cell carcinoma and some other malignant tumors are available ( "
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    ABSTRACT: SETDB1 has been established as an oncogene in a number of human carcinomas. The present study was to evaluate the expression of SETDB1 in prostate cancer (PCa) tissues and cells and to preliminarily investigate the role of SETDB1 in prostate tumorigenesis in vitro. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were used to detect the expression of SETDB1 in PCa tissues, adjacent normal tissues, benign prostatic hyperplasia (BPH) tissues, PCa cell lines and normal prostate epithelial cells. The results suggested that SETDB1 was upregulated in human PCa tissues compared with normal tissues at the mRNA and protein levels. The role of SETDB1 in proliferation was analyzed with cell counting kit-8, colony-forming efficiency and flow cytometry assays. The results indicated that downregulation of SETDB1 by siRNA inhibited PCa cell growth, and induced G0/G1 cell cycle arrest. The PCa cell migration and invasion decreased by silcencing SETDB1 which were assessed by using in vitro scratch and transwell invasion assay respectively. Our data suggested that SETDB1 is overexpressed in human PCa. Silencing SETDB1 inhibited PCa cell proliferation, migration and invasion.
    Asian Journal of Andrology 02/2014; 16(2). DOI:10.4103/1008-682X.122812 · 2.60 Impact Factor
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    • "Heterogeneity was observed in genomic regions containing genes with demonstrated potential to impact melanoma biology, such as the high level amplification (greater than 5 copies) of chromosome band 1q21 observed in Core 2 from Block 1–2. This region encompasses the gene for histone methyltransferase SETDB1, recently identified as an oncogene [12] and a candidate susceptibility gene [13] in melanoma. Detailed probe level and segmentation results from Chromosome 1 and Chromosome 17 are shown in Figure 3 and Additional file 2: Figure S2 respectively. "
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    ABSTRACT: Intratumoral heterogeneity is a major obstacle for the treatment of cancer, as the presence of even minor populations that are insensitive to therapy can lead to disease relapse. Increased clonal diversity has been correlated with a poor prognosis for cancer patients, and we therefore examined genetic, transcriptional, and functional diversity in metastatic melanoma. Amplicon sequencing and SNP microarrays were used to profile somatic mutations and DNA copy number changes in multiple regions from metastatic lesions. Clonal genetic and transcriptional heterogeneity was also assessed in single cell clones from early passage cell lines, which were then subjected to clonogenicity and drug sensitivity assays. MAPK pathway and tumor suppressor mutations were identified in all regions of the melanoma metastases analyzed. In contrast, we identified copy number abnormalities present in only some regions in addition to homogeneously present changes, suggesting ongoing genetic evolution following metastatic spread. Copy number heterogeneity from a tumor was represented in matched cell line clones, which also varied in their clonogenicity and drug sensitivity. Minor clones were identified based on dissimilarity to the parental cell line, and these clones were the most clonogenic and least sensitive to drugs. Finally, treatment of a polyclonal cell line with paclitaxel to enrich for drug-resistant cells resulted in the adoption of a gene expression profile with features of one of the minor clones, supporting the idea that these populations can mediate disease relapse. Our results support the hypothesis that minor clones might have major consequences for patient outcomes in melanoma.
    BMC Medical Genomics 10/2013; 6(1):40. DOI:10.1186/1755-8794-6-40 · 2.87 Impact Factor
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