Allelic imbalance mapping to uncover cSCC susceptibility alleles

描述(申请人提供)：摘要非黑色素瘤皮肤癌，包括基底细胞癌和鳞状细胞癌，是西方世界最常见的恶性肿瘤。我们已发表的工作表明，鳞癌的癌症易感基因在肿瘤中表现出优先的等位基因失衡，为识别这些等位基因提供了一种策略。OU最初的等位基因失衡研究在低分辨率基因分型筛查中使用了来自免疫抑制移植受者的多组SCC来确定候选易感基因。我们的数据 已发现多个基因座显示出等位基因特异性不平衡(ASI)的证据。随后，在来自散发性患者和移植受者的匹配的正常和肿瘤DNA中，对11q24上的9-Mb候选基因座进行了高分辨率的定量基因分型，结果发现了映射到11q24上160kb区域的变异，显示出显著的ASI证据。这项研究将确定ASI图谱是否是识别癌症的有用策略 风险等位基因。此外，我们将验证假设，即11q24上的最小候选基因座的等位基因变异与发生CSCC的风险增加相关，主要有以下两个目的：1.表征11q24上的最小候选基因座的遗传多样性，以识别导致所观察到的等位基因特异性失衡的变异。我们认为，驱动优先等位基因丢失的功能单元(基因、调控区、非编码RNA)的等位基因版本将比其他等位基因具有更强的肿瘤抑制能力。为了确定候选的因果变异，我们将通过11q24的定向深度测序来定位显示ASI的肿瘤中的所有等位基因变异，然后将进行计算机研究，以评估显示ASI的等位基因的潜在功能(S)。2.检测11q24位变异对宫颈鳞癌的易感性，以确定易患宫颈鳞癌的基因类型。我们将测试在肿瘤中显示优先等位基因失衡的11q24变异是否与发生鳞状细胞癌的风险有关。我们将在300名SCC患者和300名对照中对该基因座的10个变种进行分型，这些变异显示了ASI的显著证据。显示风险证据的顶级变种将在1650多例其他SCC病例和1800例对照中得到验证。这项研究的结果将确定ASI图谱的使用是否是识别癌症风险等位基因的另一种策略。这些研究的长期目标是了解11q24的变异对皮肤鳞状细胞癌的肿瘤发生和风险的作用机制，并评估它们作为皮肤鳞状细胞癌治疗或预防策略的可行性。这些研究具有很高的影响力，因为它们验证了等位基因特异性不平衡作为一种方法来识别癌症中重要的基因和易感等位基因，并有可能识别在鳞癌中重要的新基因。

DESCRIPTION (provided by applicant): Summary Non-melanoma skin cancer, which includes basal cell carcinoma and squamous cell carcinoma (SCC), is the most common malignancy in the Western world. Our published work has shown that cancer susceptibility genes for SCC exhibit preferential allelic imbalance in tumors providing a strategy to identify these alleles. Ou initial allelic imbalance studies used sets of multiple SCCs from immunosuppressed transplant recipients in low-resolution genotyping screens to identify candidate susceptibility loci. Our data have revealed multiple loci showing evidence of allele-specific imbalance (ASI). Subsequent high-resolution quantitative genotyping across a 9-Mb candidate locus on 11q24 in matched normal and tumor DNAs from both sporadic patients and transplant recipients led to the identification of variants mapping to a 160kb region on 11q24 that show significant evidence for ASI. This study will determine if ASI mapping is a useful strategy for the identification of cancer risk alleles. Furthermore, we will test the hypothesis that allelic variations within our minimal candidate locus on 11q24 are associated with an increased risk of developing cSCC in the following two aims: 1. To characterize genetic diversity at our minimal locus on 11q24 in order to identify variants driving the observed allele specific imbalance. We propose that allelic versions of the functional unit (gene, regulatory region, non-coding RNA) driving preferential allelic loss t 11q24 will have stronger tumor-suppressing abilities than other alleles. To identify candidate causal variants, we will map all allelic variants in tumors showing ASI by targeted deep-sequencing of 11q24 and then will perform in silico studies to assess potential function(s) of alleles showing ASI. 2. To test variants at 11q24 for susceptibility to cSCC in order to identify genotypes that predispose humans to cSCC. We will test whether variants at 11q24 showing preferential allelic imbalance in tumors are associated with the risk of developing SCC. We will genotype ten variants from this locus that show significant evidence of ASI in 300 SCC cases and 300 controls. Top variants showing evidence of risk will be validated in over 1650 additional SCC cases and 1800 controls. Results from this study will determine if the use of ASI mapping is another strategy for the identification of cancer risk alleles. The long-term goals of these studies are to understand the mechanisms by which the variants at 11q24 contribute to SCC tumorigenesis and risk and to evaluate their candidacy for therapeutic or preventative strategies for cutaneous SCC. These studies have high impact as they validate allele-specific imbalance as a method to identify genes and susceptibility alleles important in cancer and have the potential to identify new genes important in SCC.