Genetic Modifiers of Cancer Risk

第一个项目-他莫昔芬相关乳腺癌风险的遗传修饰剂：NSABP P1 G3-是对249名患有浸润性乳腺癌的女性（84名暴露于他莫昔芬; 165名安慰剂）中19种不同基因的39个SNP的病例/病例分析。这是通过单SNP关联和单倍型分析的无效研究。然而，在他莫昔芬（耐药基因型）的存在下出现的病例特征的等位基因的星座是不同的，在未暴露（安慰剂）的情况下。这种已发表的途径分析方法产生了一个等位基因签名，有可能作为他莫昔芬耐药性的预测生物标志物。通过NCI的PLCO癌症筛查试验，我们一直在研究胰岛素样生长因子（IGF）信号通路与晚期结直肠腺瘤风险之间的关系，数据提示IGF可能代表潜在的可改变的癌症风险因素。我们分析了800名在基线筛查时发现患有晚期结直肠腺瘤的参与者和800名匹配的非腺瘤受试者。对7个IGF相关基因（IGF 1、IGF-BP 3、ALS、IGF-1 R、IGF-BP 5、IGF 2、GH）的37个SNPs进行基因分型，并检测IGF-1、IGF-2和IGFBP-3的循环水平。后者记录了腺瘤风险增加1.7倍（95% C.I. 1.2-2.5），控制IGF-2、IGF-BP 3和许多其他协变量。这些数据已经公布。我们还证实了先前观察到的IGF-BP 3 -01（rs 2854744）之间的强相关性，以及IGF-BP 3 -07（rs6413441）与对照组中IGF-BP 3循环水平之间的新相关性。这项研究通过增加来自DCEG罕见癌症iSELECT研究的额外基因分型数据进行了扩展，该研究偶然分析了同一组DNA样本。这些数据提供了对IGF信号通路基因的更全面的询问：研究了1，338例晚期结直肠腺瘤病例和1，503例匹配对照，并在28个IGF通路基因中产生了570个单核苷酸多态性（SNP）的数据。两个SNP的关联在基于基因的多重检测校正后仍然具有统计学意义，其中一个在癌基因KRAS的内含子中，与腺瘤风险增加相关（OR/等位基因=1.36，95% CI =1.13-1.63，P=0.001），另一个在丝氨酸/苏氨酸激酶基因RPS 6 KB 1，与腺瘤风险降低相关（每个等位基因的OR =0.83，95%CI =0.73-0.95，P=0.006）。该项目现已完成。 我们开发了一系列评估骨肉瘤遗传风险因素的项目[CAS 10375]。骨肉瘤（OS）是最常见的原发性恶性骨肿瘤，多发生于青春期。作为1995年NCI和哈佛牙科学校发起的OS前瞻性病例对照研究的一部分，我们研究了与细胞生长调节有关的许多基因/途径的遗传变异。我们在两个独立的出版物中更新了OS的描述性流行病学：一个基于NCI SEER计划的美国数据，另一个基于多个国际癌症流行病学数据库。我们发表了一项关于身高和出生体重作为OS风险因素的荟萃分析。数据证实，身高是OS的一个重要危险因素。与出生体重相关的证据并不明确。我们还发表了第一个针对OS的多阶段GWAS，包括941名OS受试者和3，291名无癌症成人对照。两个位点实现了全基因组意义：GRM 4基因中6p21.3的位点（编码谷氨酸受体代谢型4; rs 1906953; P = 8.1 10-9）和基因沙漠中2p25.2的位点（rs7591996和rs 10208273; P = 1.0 10-8和2.9 10-7，分别）。目前正在分析确认OS队列。我们对诊断时有和无转移的骨肉瘤患者进行了病例-病例GWAS，确定了NFIB中与转移相关的新功能变体。我们对骨肉瘤病例中TP 53的序列分析发现，骨肉瘤个体中生殖系突变的频率高于预期。我们还参与了一个研讨会，该研讨会汇集了转移和骨肉瘤社区的关键意见领袖和专家，并专注于开发针对转移进展的治疗方法。 最后，我们提供了来自三项相关研究（遗传性乳腺癌/卵巢癌[HBOC]的病因学研究，HBOC中乳腺MRI的初步研究和国家卵巢癌预防和早期检测研究）的1，000多名BRCA 1/2突变携带者，以确定BRCA 1/2相关乳腺癌和卵巢癌的遗传修饰剂。该项目是与BRCA 1/2修饰物研究者联盟（CIMBA）的合作，该联盟已经产生了40篇同行评议的出版物和另外8篇正在审查的手稿，所有这些都集中在检测常见的，低突变率的遗传变异，这些变异在HBOC背景下改变了乳腺癌和卵巢癌的风险。该项目旨在帮助开发更精确的癌症风险分层模型，这可能使HBOC女性的癌症风险评估更准确。过去一年中影响最大的出版物是CIMBA对来自6大洲33个国家55个中心的20，000名BRCA 1和12，000名BRCA 2突变携带者的大规模基因型/表型分析（T Rebbeck et al.，JAMA 2015; 313（13）：1347-1361），其鉴定了每个基因内与乳腺癌或卵巢癌的较高或较低风险相关的多个特定区域。这项工作应该成为能够根据患者携带的特定突变就其癌症风险提供咨询的基础。

The first project -Genetic Modifiers of Tamoxifen-Related Breast Cancer Risk: NSABP P1G3- was a case/case analysis of 39 SNPs in 19 different genes among 249 women with invasive breast cancer (84 exposed to tamoxifen; 165 placebo). This was a null study by single SNP association and haplotype analysis. However, the constellation of alleles characterizing cases emerging in the presence of tamoxifen (resistant genotypes) was distinct from that in the unexposed (placebo) cases. This published pathway analysis approach generated an allelic signature that has potential as a predictive biomarker of tamoxifen resistance. This project is now complete.Using NCI's PLCO cancer screening trial, we have been investigating the relationship between the Insulin-Like Growth Factor (IGF) Signaling Pathway and Risk of Advanced Colorectal Adenoma, prompted by data suggesting that IGFs may represent potentially modifiable cancer risk factors. We have analyzed 800 participants found to have an advanced colorectal adenoma at the time of baseline screen, and 800 matched non-adenoma subjects. 37 SNPs in 7 IGF-related genes (IGF1, IGF-BP3, ALS, IGF-1R, IGF-BP5, IGF2, GH) were genotyped, and circulating levels of IGF-1, IGF-2 and IGFBP-3 were assayed. The latter documented a 1.7-fold increase in adenoma risk (95% C.I. 1.2-2.5) in highest vs. lowest quartiles of IGF-1, controlled for IGF-2, IGF-BP3 and numerous other covariates. These data have been published. We also confirmed the previously-observed strong relationship between IGF-BP3-01 (rs2854744), and a new association between IGF-BP3-07 (rs6413441) and circulating levels of IGF-BP3 among controls. This study has been expanded by adding additional genotyping data from the DCEG Rare Cancers iSELECT study which, serendipitously, analyzed the same set of DNA samples. These data provide a more comprehensive interrogation of IGF signaling pathway genes: 1,338 advanced colorectal adenoma cases and 1,503 matched controls were studied, and data generated for 570 single nucleotide polymorphisms (SNPs) in 28 IGF pathway genes. Two SNP associations remained statistically significant after a gene-based correction for multiple testing, one in an intron of the oncogene, KRAS, was associated an increased risk of adenoma (OR per allele=1.36, 95% CI =1.13-1.63, P=0.001), and the other in the serine/threonine kinase gene, RPS6KB1, was associated with a reduced risk of adenoma (OR per allele=0.83, 95% CI=0.73-0.95, P=0.006). This project is now complete. We have developed a portfolio of projects evaluating Genetic Risk Factors for Osteosarcoma [CAS 10375]. Osteosarcoma (OS), the most common malignant primary bone tumor, occurs most commonly during the adolescent growth spurt. As part of a prospective case-control study of OS initiated in 1995 with the NCI and Harvard Dental School, we studied genetic variation in many genes/pathways implicated in the cellular regulation of growth. We updated the descriptive epidemiology of OS in two separate publications: one based on US data from NCI's SEER program, and the other based on multiple international cancer epidemiology databases. We published a meta-analysis of height and birth weight as OS risk factors. The data confirmed that height is a significant risk factor for OS. The evidence related to birth weight was not definitive. We also published the first multistage GWAS targeting OS consisting of 941 OS subjects and 3,291 cancer-free adult controls. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 10-9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 10-8 and 2.9 10-7, respectively). A validation OS cohort is currently being analyzed. We performed a case-case GWAS of osteosarcoma patients with and without metastases at diagnosis which identified novel functional variants in NFIB as associated with metastasis. Our sequence analysis of TP53in osteosarcoma cases found a higher than expected frequency of germline mutations in individuals with osteosarcoma.We also contributed to a Workshop that brought together key opinion leaders and experts in the metastasis and osteosarcoma communities and which focused on developing therapeutics that target metastatic progression. Finally, we have contributed more than 1,000 BRCA1/2 mutation carriers accrued from three related studies (Etiologic Studies of Hereditary Breast/Ovarian Cancer [HBOC], Pilot Study of Breast MRI in HBOC, and the National Ovarian Cancer Prevention and Early Detection Study) to identify genetic modifiers of BRCA1/2-related breast and ovarian cancer. This project is a collaboration with the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) which has yielded 40 peer-reviewed publications and an additional 8 manuscripts under review, all focused on detecting common, low-penetrance genetic variants which modify the risk of breast and ovarian cancer in the HBOC context. This project is designed to help develop more precise cancer risk stratification models which might permit more accurate cancer risk assessment in women with HBOC. The highest impact publication during the past year has been the massive genotype/phenotype analysis of CIMBA's collection of 20,000 BRCA1 and 12,000 BRCA2 mutation carriers from 55 centers in 33 countries on 6 continents (T Rebbeck et al., JAMA 2015; 313(13):1347-1361) which identified multiple specific regions within each gene that were associated with higher or lower risks of breast or ovarian cancer. This work should form the foundation of being able to counsel patients regarding their cancer risks based on the specific mutation they carry.