Allelic imbalance mapping to uncover cSCC susceptibility alleles

描述（由申请人提供）：摘要非黑色素瘤皮肤癌，包括基底细胞癌和鳞状细胞癌（SCC），是西方世界最常见的恶性肿瘤。我们已发表的工作表明，SCC的癌症易感基因在肿瘤中表现出优先等位基因失衡，这为识别这些等位基因提供了一种策略。最初的等位基因不平衡研究使用来自免疫抑制移植受者的多个SCC组，在低分辨率基因分型筛选中鉴定候选易感基因座。我们的数据 已经揭示了多个位点显示等位基因特异性不平衡（ASI）的证据。随后在来自散发患者和移植受体的匹配正常和肿瘤DNA中的11q24上的9-Mb候选基因座上进行高分辨率定量基因分型，导致鉴定出映射到11q24上的160kb区域的变体，这些变体显示出ASI的显著证据。这项研究将确定ASI定位是否是一种有用的癌症识别策略 危险等位基因此外，我们将在以下两个目标中检验我们在11q24上的最小候选基因座内的等位基因变异与发展cSCC的风险增加相关的假设：1.描述11q24最小位点的遗传多样性，以确定导致所观察到的等位基因特异性失衡的变异。我们提出，等位基因版本的功能单位（基因，调控区，非编码RNA）驱动优先等位基因损失t11q24将有更强的肿瘤抑制能力比其他等位基因。为了鉴定候选的致病变异，我们将通过11q24的靶向深度测序来绘制显示ASI的肿瘤中的所有等位基因变异，然后将进行计算机模拟研究以评估显示ASI的等位基因的潜在功能。2.检测11q24变异体对cSCC的易感性，以确定使人类易患cSCC的基因型。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SCC的风险相关。我们将从该位点对10个变异体进行基因分型，这些变异体在300例SCC病例和300例对照中显示出ASI的显著证据。将在超过1650个额外SCC病例和1800个对照中确认显示风险证据的最常见变体。这项研究的结果将确定ASI作图的使用是否是另一种识别癌症风险等位基因的策略。这些研究的长期目标是了解11q24变异导致SCC肿瘤发生和风险的机制，并评估其用于皮肤SCC治疗或预防策略的候选资格。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鉴定癌症中重要基因和易感性等位基因的方法，并有可能鉴定SCC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.