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

• 批准号: 8243916
• 负责人: Fabienne Lesueur
• 金额: $ 5.76万
• 依托单位: INTERNATIONAL AGENCY FOR RES ON CANCER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243916
• 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; Screening procedure; 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; 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; sun protection; trait; trend; tumor; ultraviolet damage

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. PUBLIC HEALTH RELEVANCE: Malignant melanoma is a rare tumor of melanocytes that, because of its aggressive nature, causes the majority of deaths related to skin cancer. Since the mid-20th century, melanoma has become an important health problem in fair-skinned populations worldwide, since its incidence has climbed faster than any other type of malignancy. The goal of this study is the identification of new melanoma susceptibility genes and the characterization of the pathogenic sequence variants associated with increased risk of developing melanoma. Identification of susceptible individuals may aid in increasing sun protection and early detection of melanocytic tumors at the precancerous stage of the disease, altering attitudes toward sunlight and suntans, and protecting the skin from UV damage in populations at risk.

描述(由申请人提供)：一些全基因组关联研究(GWAS)已经成功地将常见的SNP与复杂性状的病因联系起来。到目前为止发现的大多数变异都会带来相对较小的风险增量(1.1-1.5倍)，并解释了只有一小部分家族聚集性。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障碍变异所致。到目前为止，对罕见变异的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对候选基因和基因组的广泛关联研究。如果罕见的变异比常见的变异有更大的影响，这应该有助于它们的检测。此外，它们的识别应该对风险评估、疾病预防和治疗产生更大的影响。然而，对罕见变种的分析是具有挑战性的，因为用于常见变种的方法力量不足。此前，我们使用乳腺癌患者和对照的突变筛查数据来证明，从截断和剪接连接变异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成从最小到最有可能对进化有害的一系列等级，然后进行Logistic回归趋势检验，以比较病例和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。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EPIC队列中登记的来自10个欧洲国家的1300多名病例和1300名匹配的对照组中，突变筛选色素沉着途径的最强候选基因。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)和已知易感基因之间的关系已经被很好地理解。CDKN2A和CDK4的高危突变由大约20%-25%的黑色素瘤倾向家庭携带。相反，色素沉着基因MC1R中的一些错义替换已被证明是中等风险或中等风险的易感等位基因，也增加了CDKN2A突变的外显率。最后，最近的两个Gwas在MC1R或同一途径的基因中发现了低外显性SNPs。相关的SNPs将不会超过家族性相对风险的12%。因此，大多数CMM的遗传易感性仍有待解释。在我们的方法在强大的候选对象上得到验证后，预计将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有关的致病序列变体的风险-频率谱的全面图像。 公共卫生相关性：恶性黑色素瘤是一种罕见的黑素细胞肿瘤，由于其侵袭性，导致了与皮肤癌相关的大部分死亡。自20世纪中叶以来，黑色素瘤已经成为全球白皮肤人群的一个重要健康问题，因为它的发病率上升得比任何其他类型的恶性肿瘤都快。这项研究的目标是识别新的黑色素瘤易感基因，并表征与黑色素瘤发病风险增加相关的致病序列变异。对易感个体的识别可能有助于在疾病的癌前阶段加强防晒和及早发现黑色素细胞肿瘤，改变人们对阳光和晒黑的态度，并在高危人群中保护皮肤免受紫外线损害。