Genetic and Pharmacogenetic Modifiers of Cancer Risk and Intervention Outcomes

Division Of Cancer Epidemiology And Genetics

Investigators

Linked publications & trials

Abstract

The first of these studies - <B>Genetic Modifiers of Tamoxifen-Related Breast Cancer Risk: NSABP P1G3 [CAS 7220]</B>- 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 pathway analysis approach generates an allelic signature that may have potential as a predictive biomarker of tamoxifen resistance. A manuscript is under review.<BR;BR>Utilizing the resources of the Prostate, Lung, Colon and Ovarian (PLCO) Cancer screening trial, we have been investigating the relationship between the <B>Insulin-Like Growth Factor (IGF) Signaling Pathway and Risk of Advanced Colorectal Adenoma [CAS 7300]</B>, prompted by data suggesting that IGFs may represent potentially modifiable cancer risk factors. We have analyzed <B>800</B>participants found to have an advanced colorectal adenoma at the time of baseline screen, and <B>800</B>matched non-adenoma subjects. Genotyping has been completed on <B>37</B>SNPs in <B>7</B>IGF-related genes (<i>IGF1, IGF-BP3, ALS, IGF-1R, IGF-BP5, IGF2</i>and <i>GH</i>), and circulating levels of IGF-1, IGF-2 and IGFBP-3 have been measured. The latter documented a <B>1.7-fold increase in adenoma risk</B>(95% C.I. 1.2-2.5) in highest vs. lowest quartiles of IGF-1, controlled for <i>IGF-2, IGF-BP3</i>and numerous other covariates. The evaluation of genetic variants as primary risk factors for advance adenoma was null, although we 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. These two SNPs decrease IGF-BP-3 levels by 222 and 148 units per minor allele (mean IGF-BP3 level 4,000 units). Manuscripts summarizing these findings are nearing completion. <BR;BR>We have developed a portfolio of projects evaluating <B>Genetic Risk Factors for Osteogenic Sarcoma [CAS10375].</B>Osteogenic sarcoma (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 cellular regulation of growth. We identified a small haplotype block that was associated with risk of OS in the <i>IGF2R</i>gene. This genomic region (near exon 16) consists of CpG islands, and functional analysis of the SNPs in this block suggested that a specific SNP associated with OS risk results in differential methylation at that SNP site. Because OS is one of the syndrome-defining malignancies in patients with germ-line <i>TP53</i>mutations (i.e., the Li-Fraumeni Syndrome), we investigated the role of germ-line genetic variants in <i>TP53</i>as OS risk factors. These data did not indicate a strong link between variation in <i>TP53</i>and OS risk, but they did provide preliminary evidence of an increased risk of OS associated with <i>TP53</i>variants IVS2+38 and Pro72Arg. We recently updated the descriptive epidemiology of OS in two separate publications: one based on US data from NCIs SEER program, and the other based on multiple international cancer epidemiology databases. A meta-analysis is currentlyunderway aimed at clarifying height and birth weight as OS risk factors. Finally, we have launched an international collaborative project which will support a genome-wide association study (GWAS) aimed at identifying genetic risk factors for OS. Collaborators include the Childrens Oncology Group, and multiple investigators in Europe and Australia. The GWAS will consist of approximately 2000 OS cases;controls will be derived from existing NCI studies.The first of these studies - <B>Genetic Modifiers of Tamoxifen-Related Breast Cancer Risk: NSABP P1G3 [CAS 7220]</B>- 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 pathway analysis approach generates an allelic signature that may have potential as a predictive biomarker of tamoxifen resistance. A manuscript is under review.<BR;BR>Utilizing the resources of the Prostate, Lung, Colon and Ovarian (PLCO) Cancer screening trial, we have been investigating the relationship between the <B>Insulin-Like Growth Factor (IGF) Signaling Pathway and Risk of Advanced Colorectal Adenoma [CAS 7300]</B>, prompted by data suggesting that IGFs may represent potentially modifiable cancer risk factors. We have analyzed <B>800</B>participants found to have an advanced colorectal adenoma at the time of baseline screen, and <B>800</B>matched non-adenoma subjects. Genotyping has been completed on <B>37</B>SNPs in <B>7</B>IGF-related genes (<i>IGF1, IGF-BP3, ALS, IGF-1R, IGF-BP5, IGF2</i>and <i>GH</i>), and circulating levels of IGF-1, IGF-2 and IGFBP-3 have been measured. The latter documented a <B>1.7-fold increase in adenoma risk</B>(95% C.I. 1.2-2.5) in highest vs. lowest quartiles of IGF-1, controlled for <i>IGF-2, IGF-BP3</i>and numerous other covariates. The evaluation of genetic variants as primary risk factors for advance adenoma was null, although we 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. These two SNPs decrease IGF-BP-3 levels by 222 and 148 units per minor allele (mean IGF-BP3 level 4,000 units). Manuscripts summarizing these findings are nearing completion. <BR;BR>We have developed a portfolio of projects evaluating <B>Genetic Risk Factors for Osteogenic Sarcoma [CAS10375].</B>Osteogenic sarcoma (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 cellular regulation of growth. We identified a small haplotype block that was associated with risk of OS in the <i>IGF2R</i>gene. This genomic region (near exon 16) consists of CpG islands, and functional analysis of the SNPs in this block suggested that a specific SNP associated with OS risk results in differential methylation at that SNP site. Because OS is one of the syndrome-defining malignancies in patients with germ-line <i>TP53</i>mutations (i.e., the Li-Fraumeni Syndrome), we investigated the role of germ-line genetic variants in <i>TP53</i>as OS risk factors. These data did not indicate a strong link between variation in <i>TP53</i>and OS risk, but they did provide preliminary evidence of an increased risk of OS associated with <i>TP53</i>variants IVS2+38 and Pro72Arg. We recently updated the descriptive epidemiology of OS in two separate publications: one based on US data from NCIs SEER program, and the other based on multiple international cancer epidemiology databases. A meta-analysis is currentlyunderway aimed at clarifying height and birth weight as OS risk factors. Finally, we have launched an international collaborative project which will support a genome-wide association study (GWAS) aimed at identifying genetic risk factors for OS. Collaborators include t [summary truncated at 7800 characters]