权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

A new approach to identify rare genetic variants influencing melanoma risk

识别影响黑色素瘤风险的罕见遗传变异的新方法

基本信息

批准号：
8433983
负责人：
Fabienne Lesueur
金额：
$ 5.41万
依托单位：
INTERNATIONAL AGENCY FOR RES ON CANCER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433983
关键词：
Accounting Alleles Attitude Biochemical Pathway Bioinformatics Blood specimen Breast CDK4 gene CDKN2A gene CHEK2 gene Cancer Control Cancer Patient Cancer and Nutrition Candidate Disease Gene Categories Cell Cycle Cessation of life Characteristics Chronic Disease Classification Code Collection Complex Computer Simulation Country Cutaneous Melanoma DNA Repair Data Detection Development Diet and Nutrition Disease Early Diagnosis Early treatment Enrollment Environmental Risk Factor Epidemiology Etiology European Exposure to Eye Family Family Study Freckles Frequencies Gene Frequency General Population Genes Genetic Genetic Predisposition to Disease Genetic screening method Genome Goals Hair Health Hereditary Melanoma High-Risk Cancer Incidence Individual Integration Host Factors International International Agency for Research on Cancer Investigation Laboratories Lead Logistic Regressions Malignant Neoplasms Melanocytic Neoplasm Melanocytic nevus Methods Minority Modeling Molecular Biology Morphology Mutation Nature Nested Case-Control Study Nevus Oncogenes Operative Surgical Procedures Outcome Participant Pathogenicity Pathway interactions Patients Penetrance Performance Phenotype Photosensitivity Phylogenetic Analysis Pigmentation physiologic function Pilot Projects Population Populations at Risk Predisposition Premalignant Probability Process Proteins RNA Splicing Relative Risks Risk Risk Assessment Risk Estimate Scanning Scheme Sequence Alignment Series Skin Skin Cancer Skin Pigmentation Staging Study models Sun Exposure Sunlight Susceptibility Gene TYRP1 gene Technology Testing Ultraviolet Rays Validation Variant Weight advanced disease base case control clinical practice cohort design disorder prevention exome sequencing genetic epidemiology genetic variant genome wide association study high risk improved lifestyle factors loss of function mutation malignant breast neoplasm melanocyte melanoma novel novel strategies outcome forecast programs prospective risk variant screening sun protection trait trend tumor ultraviolet damage

项目摘要

DESCRIPTION (provided by applicant): A number of genome-wide association studies (GWAS) have successfully implicated common SNPs in the etiology of complex traits. Most variants identified so far confer relatively small increments in risk (1.1-1.5-fold), and explain oly a small proportion of familial clustering. Recent studies have demonstrated that common diseases can be due to dysfunctional variants with a wide spectrum of allele frequencies. So far, rare variants studies have been limited to a handful of phenotypes and genes, but the advancement of sequencing technologies should lead to widespread association studies of candidate genes and genomes. If rare variants have larger effects than common variants, this should aid in their detection. Also their identification should have a greater impact on risk assessment, disease prevention and treatment. However, the analysis of rare variants is challenging since methods used for common variants are underpowered. Previously, we used data from mutation screening of breast cancer patients and controls to demonstrate the ability to detect evidence of pathogenicity from both truncating and splice junction variants and rare missense substitutions. The method involves stratifying rare missense substitutions observed in cases and/or in controls into a series of grades ordered from least to most likely to be evolutionarily deleterious, followed by a logistic regression trend test to compare the frequency distributions of the grades of variants in cases versus controls. The original model was developed to assess the pathogenicity of missense substitutions in breast cancer-related genes. Here we propose to test the efficiency of our analysis strategy to cutaneous malignant melanoma (CMM). To identify novel risk alleles, we will mutation screen the strongest candidate genes of the pigmentation pathway in over 1,300 cases and 1,300 matched controls from 10 European countries enrolled in the EPIC cohort. CMM provides a unique model for studies of gene-gene and gene-environmental interactions in the development of multifactorial diseases, since relationships between the major environmental factor (exposure to solar UV radiation) and known susceptibility genes are reasonably well understood. High-risk mutations in CDKN2A and CDK4 are carried by about 20-25% of melanoma-prone families. In contrast, some missense substitutions in the pigmentation gene MC1R have been proven to be modest-risk or intermediate-risk susceptibility alleles, and also to increase the penetrance of CDKN2A mutations. Finally, two recent GWAS identified low- penetrance SNPs in MC1R or in genes of the same pathway. Associated SNPs will account for no more than 12% of the Familial Relative Risk. Thus, the majority of the genetic susceptibility to CMM remains to be explained. After validation of our method on strong candidates, massive parallel sequencing of genes of entire biochemical pathways is envisaged to generate a comprehensive picture of the risk-frequency spectrum for pathogenic sequence variants involved in susceptibility to melanoma.

描述（由申请人提供）：许多全基因组关联研究（GWAS）已成功地将常见的 SNP 与复杂性状的病因学联系起来。迄今为止发现的大多数变异都带来相对较小的风险增量（1.1-1.5倍），并且只能解释一小部分家族聚集。最近的研究表明，常见疾病可能是由于具有广泛等位基因频率的功能失调变异引起的。到目前为止，罕见变异研究仅限于少数表型和基因，但测序技术的进步应该会导致候选基因和基因组的广泛关联研究。如果罕见变异比常见变异具有更大的影响，这应该有助于检测它们。它们的识别也应对风险评估、疾病预防和治疗产生更大的影响。然而，由于用于常见变体的方法动力不足，因此对罕见变体的分析具有挑战性。此前，我们使用乳腺癌患者和对照的突变筛查数据来证明从截短和剪接变异体以及罕见的错义替换中检测致病性证据的能力。该方法包括将病例和/或对照中观察到的罕见错义替换分层为一系列等级，按从最不可能到最可能对进化有害的顺序排列，然后进行逻辑回归趋势测试，以比较病例与对照中变异等级的频率分布。最初的模型是为了评估乳腺癌相关基因错义替换的致病性而开发的。在这里，我们建议测试我们的分析策略对皮肤恶性黑色素瘤（CMM）的效率。为了识别新的风险等位基因，我们将在来自 10 个欧洲国家的 EPIC 队列中的 1,300 多个病例和 1,300 名匹配对照中突变筛选色素沉着途径最强的候选基因。 CMM 为研究多因素疾病发展中的基因-基因和基因-环境相互作用提供了一个独特的模型，因为主要环境因素（暴露于太阳紫外线辐射）与已知易感基因之间的关系已得到相当充分的了解。约 20-25% 的黑色素瘤易发家族携带 CDKN2A 和 CDK4 的高风险突变。相比之下，色素沉着基因MC1R中的一些错义取代已被证明是中等风险或中等风险的易感性等位基因，并且也会增加CDKN2A突变的外显率。最后，最近的两项 GWAS 在 MC1R 或相同途径的基因中发现了低外显率 SNP。相关 SNP 占家族相对风险的比例不超过 12%。因此，大多数 CMM 的遗传易感性仍有待解释。在对强有力的候选者验证我们的方法后，设想对整个生化途径的基因进行大规模并行测序，以生成与黑色素瘤易感性相关的致病序列变异的风险频谱的全面图景。