STUDIES IN COLORECTAL AND RELATED CANCERS

结直肠癌及相关癌症的研究

• 批准号: 7723455
• 负责人: Robert C. Elston
• 金额: $ 1.82万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723455
• 关键词: 15q14; 17p13.3; Acetylation; Affect; Age; Alleles; American; Ashkenazim; BRCA2 gene; Breast; Cancer Etiology; Candidate Disease Gene; Carcinogen Metabolism; Chromosomes; Classification; Clinical; Colon; Colonic Neoplasms; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Computer Retrieval of Information on Scientific Projects Database; Confidence Intervals; Data; Disease; Disease regression; Drug Metabolic Detoxication; Enzymes; European; Exposure to; Family; Family history of; Funding; Genes; Genotype; Genus Cola; Grant; Heterogeneity; Histopathology; Inherited; Institution; Intake; Link; Malignant Neoplasms; Measures; Meat; Meta-Analysis; Minority; Modeling; Modification; Numbers; Odds Ratio; Pathway interactions; Phenotype; Polyps; Population; Predisposition; Proteins; Research; Research Personnel; Resources; Risk; Sampling; Scanning; Siblings; Smoking; Source; Statistically Significant; Subgroup; Susceptibility Gene; Syndrome; United States National Institutes of Health; Variant; cancer diagnosis; cancer risk; design; genetic variant; genome-wide linkage; heterocyclic aromatic amines; human NAT2 protein; interest; kindred; malignant breast neoplasm; mortality; polyposis; size; statistics

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Americans and is the second leading cause of cancer mortality. Only a minority ( approximately 5%) of familial CRC can be explained by known genetic variants. To identify susceptibility genes for familial colorectal neoplasia, the colon neoplasia sibling study conducted a comprehensive, genome-wide linkage scan of 194 kindreds. Clinical information (histopathology, size and number of polyps, and other primary cancers) was used in conjunction with age at onset and family history for classification of the families into five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancer) prior to analysis. By expanding the traditional affected-sib-pair design to include unaffected and discordant sib pairs, analytical power and robustness to type I error were increased. Sib-pair linkage statistics and Haseman-Elston regression identified 19 linkage peaks, with interesting results for chromosomes 1p31.1, 15q14-q22, 17p13.3, and 21. At marker D1S1665 (1p31.1), there was strong evidence for linkage in the multiple-cancer subgroup (p = 0.00007). For chromosome 15q14-q22, a linkage peak was identified in the full-sample (p = 0.018), oligopolyposis (p = 0.003), and young (p = 0.0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome (HMPS) in families of Ashkenazi descent. We provide compelling evidence linking this region in families of European descent with oligopolyposis and/or young age at onset (<or=51) phenotypes. We found linkage to BRCA2 in the colon/breast phenotypic subgroup and identified a second locus in the region of D21S1437 segregating with, but distinct from, BRCA2. Linkage to 17p13.3 at marker D17S1308 in the breast/colon subgroup identified HIC1 as a candidate gene. We previously identified in the severe histopathology subgroup the chromosomal region 9q22.2-31.2 as harboring a susceptibility locus for colorectal neoplasia. We conclude that there remains an unidentified susceptibility locus in the region. Further study of this region definitely excludes the possibility of the TGFBR1*6A allele increasing the risk of colorectal neoplasia in our sample population. A recent study validating linkage of colorectal cancer to chromosome 9q also excluded the TGFBR1*6A allele as a disease-causing variant in that sample. In view of the familial aggregation of colon and breast cancer, we performed a meta-analysis of variants that may underly susceptibility to breast cancer. The N-acetyltransferase 2 gene (NAT2) product is an enzyme important in carcinogen metabolism via activation and detoxification pathways. We extracted all relevant data to examine evidence for a main effect (i.e., the effect in a model that does not include any interactions) of NAT2 phenotype and genotype on breast cancer risk. We summarized the evidence for modification by smoking and meat intake, sources of exposure to aromatic and heterocyclic amines, respectively, which are metabolized by NAT2. We identified seven studies that measured NAT2 phenotype and 20 studies that deduced phenotype via genotyping. We found no evidence for heterogeneity (Cochran's Q statistic p=0.74) and no statistically significant increased risk from NAT2 acetylation (slow/rapid) for breast cancer (summary odds ratio=1.02, 95% confidence interval: 0.95, 1.08). These results suggest that there is no overall association between the NAT2 slow- or rapid-acetylation phenotype and breast cancer risk. However, some evidence suggests that smoking may modify this association.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 结直肠癌（CRC）是美国人第三大最常见的癌症，也是癌症死亡的第二大原因。只有少数（约5%）的家族性CRC可以通过已知的遗传变异来解释。为了确定家族性结直肠肿瘤的易感基因，结肠肿瘤同胞研究对194个基因进行了全面的全基因组连锁扫描。临床信息（组织病理学、息肉大小和数量以及其他原发性癌症）与发病年龄和家族史结合使用，在分析前将家族分为5个表型亚组（严重组织病理学、寡息肉病、年轻、结肠/乳腺和多发性癌症）。通过扩展传统的受影响的同胞对设计，包括未受影响的和不一致的同胞对，分析能力和稳健性的I型错误增加。同胞对连锁统计和Haseman-Elston回归确定了19个连锁峰，染色体1p31.1，15 q14-q22，17p13.3和21的有趣结果。在标记D1 S1665（1p31.1），有强有力的证据表明在多癌亚组中存在连锁关系（p = 0.00007）。对于染色体15 q14-q22，在全样本（p = 0.018）、寡聚症（p = 0.003）和年轻（p = 0.0009）表型中鉴定出连锁峰。该区域包括与德系犹太血统家族中的遗传性混合性息肉病综合征（HMPS）相关的HMPS/CRAC 1基因座。我们提供了令人信服的证据，该地区在欧洲血统的家庭与寡息肉病和/或年轻的发病年龄（<或=51）表型。我们在结肠/乳腺表型亚组中发现了与BRCA 2的连锁，并在D21 S1437区域中发现了与BRCA 2分离但不同的第二个位点。在乳腺/结肠亚组中，与标记D17 S1308处的17p13.3的连锁确定了H1N1为候选基因。我们以前在严重的组织病理学亚组中确定染色体区域9q22.2-31.2为结直肠肿瘤的易感基因座。 我们的结论是，仍然有一个不明的易感位点在该地区。对该区域的进一步研究明确排除了TGFBR 1 *6A等位基因增加我们样本人群中结直肠肿瘤风险的可能性。最近的一项研究证实了结直肠癌与染色体9 q的连锁关系，也排除了TGFBR 1 *6A等位基因作为该样本中的致病变体。 鉴于结肠癌和乳腺癌的家族聚集性，我们对可能导致乳腺癌易感性的变异进行了荟萃分析。 N-乙酰基转移酶2基因（NAT 2）产物是通过活化和解毒途径在致癌物代谢中重要的酶。我们提取了所有相关数据来检查主效应的证据（即，在不包括任何相互作用的模型中的作用）NAT 2表型和基因型对乳腺癌风险的影响。我们总结了通过吸烟和肉类摄入，暴露于芳香族和杂环胺，分别由NAT 2代谢的修改的证据。我们确定了7项测量NAT 2表型的研究和20项通过基因分型推断表型的研究。我们没有发现异质性的证据（Cochran's Q统计p=0.74），也没有发现乳腺癌的NAT 2乙酰化（慢/快）的统计学显著增加风险（汇总比值比=1.02，95%置信区间：0.95，1.08）。这些结果表明，NAT 2缓慢或快速乙酰化表型与乳腺癌风险之间没有总体关联。然而，一些证据表明，吸烟可能会改变这种关联。