Genetics of mammographic density and breast cancer risk in Latinas

摘要 乳房X光摄影密度(MD)是乳腺癌的强烈危险因素，家庭研究表明它高度 可遗传的。全基因组关联研究(GWAS)已经确定了MD的少量基因座，其中一些 这与乳腺癌的风险有重叠。然而，乳腺癌的大部分遗传性仍未得到解释。 解释密度和乳腺癌风险之间重叠的潜在生物学仍然很差。 明白了。 这项提议将支持Elad Ziv博士继续乳房X光摄影密度遗传学的科学工作。 并继续指导临床医生研究癌症的翻译遗传学研究。作为该计划的一部分 在当前的K24周期中，Ziv博士和他的同事们研究了乳腺癌和MD的遗传学 拉丁裔女性。他们已经通过混合作图和GWAS确定了一个非常强的关联 染色体6q25上的核苷酸多态性(SNP)。该SNP的次要等位基因At与 显著降低患乳腺癌的风险(杂合子的优势比为0.6，纯合子的优势比为0.2)。 他们还发现，次要等位基因与乳房X光照相密度的显著降低有关； 比较普通等位基因纯合女性和低风险次要等位基因纯合女性， 乳房X光摄影密度中位数分别从16%降至8%。这个SNP几乎被发现 仅限于拉丁裔妇女，因为它起源于该地区的土著美国人。 这些结果证明了在非高加索人群中对复杂性状进行遗传研究的价值。 作为这个项目更新的一部分，他们的目标是延长这些研究。他们将把重点放在拉丁裔，这是一种相对 研究不足的人口，在那里他们开发了独特的资源，包括一个大的GWA和整个 外显子组测序数据。首先，他们将研究6q25基因座上的罕见变异是否可能是 在拉丁裔女性中与MD有关。他们将对他们所在的区域进行有针对性的捕获和排序 以前被发现与乳腺癌和密度有关，他们将进行罕见的变异 关联测试。其次，他们将使用来自患有乳腺癌和对照的拉丁裔妇女的Gwas数据来 确定哪些基因和途径可能与乳房密度和乳房重叠有关 癌症风险。第三，他们将使用他们的外显子组测序项目(R01CA184545)的数据来研究 基因编码区的罕见变异是否可能是MD和乳房共同遗传性的基础 癌症。 齐夫博士还将继续指导初级教师、博士后研究员、住院医生和从事研究的学生。 被辅导者将致力于本提案中列出的目标以及其他几个关于基因的大型项目 乳腺癌易感性、钼靶密度遗传学和多发性骨髓瘤遗传学。

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.