Samuel Broder

Estrogen Receptor Genotypes and Haplotypes Associated with Breast Cancer Risk

Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen. We studied single nucleotide polymorphisms (SNPs) in estrogen receptors in 615 healthy subjects and 1011 individuals with histologically confirmed breast cancer, all from New York City. We analyzed 13 SNPs in the progesterone receptor gene (PGR), 17 SNPs in estrogen receptor 1 gene (ESR1), and 8 SNPs in the estrogen receptor 2 gene (ESR2). We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), ∼ O.4; 95% confidence interval (CI), 0.2–0.8; P < 0.01]. Another haplotype was associated with an increased risk of breast cancer (OR, 2.1; 95% CI, 1.2–3.8; P < 0.05). A unique risk haplotype was present in ∼7% of older Ashkenazi Jewish study subjects (OR, 1.7; 95% CI, 1.2–2.4; P < 0.003). We narrowed the ESR1 risk haplotypes to the promoter region and first exon. We define several other haplotypes in Ashkenazi Jews in both ESR1 and ESR2 that may elevate susceptibility to breast cancer. In contrast, we found no association between any PGR variant or haplotype and breast cancer. Genetic epidemiology study replication and functional assays of the haplotypes should permit a better understanding of the role of steroid receptor genetic variants and breast cancer risk.

Multiple variants in toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection

BACKGROUND/AIMS Seven genomic loci, implicated by single nucleotide polymorphisms (SNPs), have recently been associated with progression to advanced fibrosis (fibrosis risk) in patients with chronic hepatitis C virus. Other variants in these loci have not been examined but may be associated with fibrosis risk independently of or due to linkage disequilibrium with the original polymorphisms. METHODS We carried out dense genotyping and association testing of additional SNPs in each of the 7 regions in Caucasian case control samples. RESULTS We identified several SNPs in the toll-like receptor 4 (TLR4) and syntaxin binding protein 5-like (STXBP5L) loci that were associated with fibrosis risk independently of the original significant SNPs. Haplotypes consisting of these SNPs in TLR4 and STXBP5L were strongly associated with fibrosis risk (global P=3.04 x 10(-5) and 4.49 x 10(-6), respectively). CONCLUSIONS Multiple variants in TLR4 and STXBP5L genes modulate risk of liver fibrosis. These findings are of relevance for understanding the pathogenesis of HCV-induced liver disease in Caucasians and may be extended to other ethnicities as well.

Whole genomes: the foundation of new biology and medicine

Our genomic DNA sequence provides a unique glimpse of the provenance and evolution of our species, the migration of peoples, and the causation of disease. Understanding the genome may help resolve previously unanswerable questions, including perhaps which human characteristics are innate or acquired. Such an understanding will make it possible to study how genomic DNA sequence varies among populations and among individuals, including the role of such variation in the pathogenesis of important illnesses and responses to pharmaceuticals. The study of the genome and the associated proteomics of free-living organisms will eventually make it possible to localize and annotate every human gene, as well as the regulatory elements that control the timing, organ-site specificity, extent of gene expression, protein levels, and post-translational modifications. For any given physiological process, we will have a new paradigm for addressing its evolution, development, function, and mechanism.

A Single-Tube Quantitative Assay for mRNA Levels of Hormonal and Growth Factor Receptors in Breast Cancer Specimens

Knowledge of estrogen receptor (ER) and progesterone receptor (PR) status has been critical in the evolution of modern targeted therapy of breast cancer and remains essential for making informed therapeutic decisions. Recently, growth factor receptor HER2/neu (ERBB2) status has made it possible to provide another form of targeted therapy linked to the overexpression of this protein. Presently, pathologists determine the receptor status in formalin-fixed, paraffin-embedded sections using subjective, semiquantitative immunohistochemistry (IHC) assays and quantitative fluorescence in situ hybridization for HER2. We developed a single-tube multiplex TaqMan (mERPR+HER2) assay to quantitate mRNA levels of ER, PR, HER2, and two housekeeping genes for breast cancer formalin-fixed, paraffin-embedded sections. Using data from the discovery sample sets, we evaluated IHC-status-dependent cutoff-point and IHC-status-independent clustering methods for the classification of receptor status and then validated these results with independent sample sets. Compared with IHC-status, the accuracies of the mERPR+HER2 assay with the cutoff-point classification method were 0.98 (95% CI: 0.97-1.00), 0.92 (95% CI: 0.88-0.95), and 0.97 (95% CI: 0.95-0.99) for ER, PR, and HER2, respectively, for the validation sets. Furthermore, the areas under the receiver operating-characteristic curves were 0.997 (95% CI: 0.994-1.000), 0.967 (95% CI: 0.949-0.985), and 0.968 (95% CI: 0.915-1.000) for ER, PR, and HER2, respectively. This multiplex assay provides a sensitive and reliable method to quantitate hormonal and growth factor receptors.

Cures for the Third World's problems The application of genomics to the diseases plaguing the developing world may have huge medical and economic benefits for those countries and might even prevent armed conflict

The sequencing of the human genome has been heralded as a major milestone in biological science that will, without doubt, provide fundamentally new ways of studying the human condition (Lander et al ., 2001; Subramanian et al ., 2001a; Venter et al ., 2001). Yet, for a substantial portion of the worlds population, the human condition is defined by diseases such as malaria, tuberculosis, cholera, filariasis, soil‐transmitted helminthiasis, trypanosomiais, schistosomiasis, onchocerciasis, yellow fever, dengue, measles and rotaviral gastroenteritis. And, of course, the pandemic of HIV/AIDS looms as an ever‐increasing threat over the Third World. It is in the developing countries where genome science could make the biggest impact. Indeed, the World Health Organization, in its report on ‘Genomics and World Health’ published this April, sees it the same way. ‘Within the next few years, new diagnostic agents, vaccines and therapeutic agents will likely be available for communicable diseases,’ the reports authors expect, and state that ‘the time has come to plan how this technology and its potential clinical advances can be distributed fairly among the worlds population. Otherwise, this new field will simply widen the gap in health care between the rich and poor countries of the world’ (WHO, 2002). Moreover, the diseases of the developing world?sometimes referred to as tropical diseases?can no longer be viewed in a purely medical or public health context. There is an emerging body of evidence that suggests that infectious diseases pose a major risk to the economic survival of many Third World nations. Even more striking, recent data suggest that some of these diseases may have wider implications for geopolitical stability or the probability that a nation will experience armed conflict. > It is in the developing countries where genome science could make the biggest impact Clearly, genomics is already advancing our knowledge of infectious …

Genome-based biomarkers for adverse drug effects, patient enrichment and prediction of drug response, and their incorporation into clinical trial design

Classic examples of pharmacogenomic biomarkers for drug efficacy include genetic variation in the drug target (including its expression level) and drug metabolizing enzymes (DMEs). Recent US FDA approvals of tests for cytochrome P450 2D6/2C9 and uridine diphosphate glucuronsyltransferase (UGT)1A1 have given regulatory endorsement to biomarkers that can improve drug safety by identifying individuals at risk for drug toxicity. Markers that predict risk for disease can identify patients who will have a greater than average benefit from therapy. This creates a new opportunity to enrich clinical trials with patients who are likely to have more events and to achieve earlier drug approval. Markers that predict for risk of cardiovascular, thrombotic and liver diseases may also identify a subset of individuals at substantially elevated risk for adverse drug effects. The adaptive clinical trial design provides a mechanism for incorporating genomic information during clinical trials, while providing sufficient time for diagnostic product development and co-registration with a new drug application.