Genetics of mammographic density and breast cancer risk in Latinas

拉丁裔乳房 X 光密度和乳腺癌风险的遗传学

• 批准号: 10218063
• 负责人: Elad Ziv
• 金额: $ 18.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-09 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218063
• 关键词: Alleles; Alternative Splicing; Area; Biology; Breast Cancer Genetics; Breast Cancer Risk Factor; Cancer Control; Chromosomes; Code; Complex; Data; Data Set; Epidemiology; Estrogen receptor negative; European; Faculty; Family Study; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genotype-Tissue Expression Project; Heritability; Heterozygote; Homozygote; Indigenous American; Joints; Latina; Malignant Neoplasms; Mammary Gland Parenchyma; Mammographic Density; Mentors; Mexican; Minor; Multiple Myeloma; Nucleic Acid Regulatory Sequences; Odds Ratio; Pathway interactions; Play; Population; Postdoctoral Fellow; Quantitative Trait Loci; RNA Splicing; Regulatory Element; Reporting; Research; Research Personnel; Residual state; Resources; Risk; Risk Reduction; Role; Single Nucleotide Polymorphism; Spliced Genes; Students; Testing; Twin Studies; Variant; Woman; Work; admixture mapping; base; breast cancer family; breast density; density; exome sequencing; genome wide association study; malignant breast neoplasm; protective allele; rare variant; trait; translational genetics

ABSTRACT Mammographic density (MD) is a strong risk factor for breast cancer and family studies suggest it is highly heritable. Genome wide association studies (GWAS) have identified a modest number of loci for MD, some of which overlap with breast cancer risk. However, most of the heritability of breast cancer remains unexplained and the underlying biology that explains the overlap between density and breast cancer risk remains poorly understood. This proposal will support Dr. Elad Ziv to continue scientific work on the genetics of mammographic density and to continue to mentor clinician investigators in translational genetic studies of cancer. As part of the current cycle of this K24, Dr. Ziv and his colleagues have investigated the genetics of breast cancer and MD in Latina women. They have identified, via admixture mapping and GWAS, a very strong association for a single nucleotide polymorphism (SNP) on chromosome 6q25. The minor allele at of this SNP is associated with substantially reduced risk of breast cancer (Odds ratio of 0.6 for heterozygotes and 0.2 for homozygotes). They also found that the minor allele is associated with a substantial reduction of mammographic density; comparing women homozygous for the common allele vs. women homozygous for the low risk minor allele, the median percent mammographic density is reduced from 16% to 8%, respectively. This SNP is found almost exclusively in Latina women since this it originates in the Indigenous American populations from that region. These results demonstrate the value of genetic studies in non-Caucasian populations for complex traits. As part of the renewal for this project, they aim to extend these studies. They will focus on Latinas, a relatively understudied population, where they have developed unique resources including a large GWAS and whole exome sequencing data. First, they will investigate the possibility that rare variants at the 6q25 locus are associated with MD in Latina women. They will perform targeted capture and sequencing of the region they have previously found to be associated with breast cancer and density and they will perform rare variant association tests. Second, they will use GWAS data from Latina women with breast cancer and controls to determine what genes and pathways might be involved in the overlap between breast density and breast cancer risk. Third, they will use data from their exome sequencing project (R01CA184545) to investigate whether rare variants in coding regions in genes might underlie the shared heritability between MD and breast cancer. Dr. Ziv will also continue to mentor junior faculty, post-doctoral fellows, residents and students in research. Mentees will work on the aims listed in this proposal and on several other large projects on genetic susceptibility to breast cancer, genetics of mammographic density and genetics of multiple myeloma.

摘要 乳腺摄影密度（MD）是乳腺癌的一个强有力的危险因素，家族研究表明， 遗传的全基因组关联研究（GWAS）已经确定了MD的适度数量的基因座，其中一些是 与乳腺癌风险重叠。然而，乳腺癌的大部分遗传性仍然无法解释 而解释密度和乳腺癌风险之间重叠的基础生物学仍然很差 明白 该提案将支持Elad Ziv博士继续进行乳房X线摄影密度遗传学方面的科学工作 并继续指导临床研究人员进行癌症的转化遗传学研究。的一部分 Ziv博士和他的同事们研究了乳腺癌和MD的遗传学， 拉丁女人。他们已经通过混合映射和GWAS确定了一个非常强的关联， 染色体6 q25上的核苷酸多态性（SNP）。该SNP的次要等位基因与以下相关： 显著降低乳腺癌风险（杂合子的比值比为0.6，纯合子为0.2）。 他们还发现，次要等位基因与乳房X线摄影密度的大幅降低有关; 比较常见等位基因纯合的女性与低风险次要等位基因纯合的女性， 乳房X线摄影密度百分比中位数分别从16%降低到8%。这种SNP几乎 这是拉丁美洲妇女的专属权利，因为它起源于该地区的美洲土著人口。 这些结果证明了在非高加索人群中进行复杂性状遗传研究的价值。 作为该项目更新的一部分，他们的目标是扩大这些研究。他们将专注于拉丁美洲，一个相对 在那里，他们开发了独特的资源，包括一个大型的GWAS和整个 外显子组测序数据。首先，他们将研究6 q25基因座上的罕见变异是否有可能是一种基因突变。 与拉丁裔女性的MD有关。他们将进行有针对性的捕获和测序的区域， 以前发现与乳腺癌和密度有关，他们将进行罕见的变异， 联想测试其次，他们将使用来自拉丁美洲乳腺癌妇女和对照组的GWAS数据， 确定哪些基因和途径可能参与乳腺密度和乳腺癌之间的重叠， 癌症风险。第三，他们将使用外显子组测序项目（R 01 CA 184545）的数据来研究 基因编码区的罕见变异是否可能是MD和乳腺癌之间共有遗传性的基础， 癌 博士Ziv还将继续指导初级教师，博士后研究员，居民和学生的研究。 受指导者将致力于本提案中列出的目标以及其他几个关于遗传学的大型项目。 乳腺癌易感性、乳腺X线密度遗传学和多发性骨髓瘤遗传学。

项目成果

Using Breast Cancer Risk Associated Polymorphisms to Identify Women for Breast Cancer Chemoprevention.

使用乳腺癌风险相关的多态性来识别乳腺癌化学预防的女性。

• DOI: 10.1371/journal.pone.0168601
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ziv E;Tice JA;Sprague B;Vachon CM;Cummings SR;Kerlikowske K
• 通讯作者: Kerlikowske K

Joint relative risks for estrogen receptor-positive breast cancer from a clinical model, polygenic risk score, and sex hormones.

• DOI: 10.1007/s10549-017-4430-2
• 发表时间: 2017-11
• 期刊: Breast cancer research and treatment
• 影响因子: 3.8
• 作者: Shieh Y;Hu D;Ma L;Huntsman S;Gard CC;Leung JWT;Tice JA;Ziv E;Kerlikowske K;Cummings SR
• 通讯作者: Cummings SR

Interval breast cancers - insights into a complex phenotype.

• DOI: 10.1038/s41571-020-0327-9
• 发表时间: 2020-03
• 期刊: NATURE REVIEWS CLINICAL ONCOLOGY
• 影响因子: 78.8
• 作者: Shieh, Yiwey;Ziv, Elad;Kerlikowske, Karla
• 通讯作者: Kerlikowske, Karla

Analytic pipelines to assess the relationship between immune response and germline genetics in human tumors.

• DOI: 10.1016/j.xpro.2022.101809
• 发表时间: 2022-12-16
• 期刊: STAR PROTOCOLS
• 作者: Sayaman, Rosalyn W.;Saad, Mohamad;Heimann, Carolina;Hu, Donglei;Kunji, Khalid;Roelands, Jessica;Wolf, Denise M.;Huntsman, Scott;Ceccarelli, Michele;Thorsson, Vesteinn;Ziv, Elad;Bedognetti, Davide
• 通讯作者: Bedognetti, Davide

Recent shifts in the genomic ancestry of Mexican Americans may alter the genetic architecture of biomedical traits.

• DOI: 10.7554/elife.56029
• 发表时间: 2020-12-29
• 期刊: eLife
• 影响因子: 7.7
• 作者: Spear ML;Diaz-Papkovich A;Ziv E;Yracheta JM;Gravel S;Torgerson DG;Hernandez RD
• 通讯作者: Hernandez RD