The goal of the laboratory is to develop new approaches to the study of the genetic basis of cancer and its outcomes, such as infectious complications. The major focus has been on annotating candidate genes, drawn from key pathways in innate immunity and cancer biology, such as telomere stability or nutrient transport (i.e., Vitamin C sodium dependent transport). Specifically, the laboratory has developed approaches to identify and validate common genetic variants, most often, single nucleotide polymorphisms, SNPs, in an effort to define common ancestral haplotypes. In turn, haplotypes as well as SNPs with defined functional consequences (i.e., alteration in function or expression) are applied to studies to determine genetic factors contributing to cancer and its outcomes. We have taken the candidate gene approach, initially with a bias towards selecting known polymorphisms which influence either the level or functional activity of the molecule but recently, adopting an approach that seeks to capture common, ancestral haplotypes.We have invested considerable effort in collecting and analyzing cohorts of subjects with one or more breach in host immune system. Consequently, we have investigated the influence of variant genotypes of molecules of innate immunity on disease susceptibility and outcome in immunocompromised patients. Under the stress of losing a major component of host defense (i.e., neutropenia or an absent respiratory burst- which is characteristic of a rare inherited defect in phagocytic cells, known as chronic granulomatous disease), observed differences in phenotypic expression of disease might be related to polymorphisms in either a regulatory or structural region of primitive immune molecules, such as cytokines, Fc receptors, lectins and interleukins. For instance, we have completely re-sequenced the mannose binding lectin gene, MBL2 and characterized common and uncommon variants. In the process, we have observed that a set of three 'balanced polymorphisms' reside on restricted haplotypes and their distribution across the world (n=30 populations from CEPH Human Diversity Panel) suggest differential patterns of adaptation and selection. Observations in population genetics are critical for understanding the molecular epidemiology of a range of diseases (cancers, infections and autoimmune diseases) associated with MBL2 variants. We have also studied immune variants in other models diseases, such as sickle cell anemia, which also are characterized by a primary defect but clearly modified by secondary genes, such as VCAM1 and the risk for stroke. Because variants are co-inherited as haplotypes from shared ancestors, it is possible to select a subset of markers, namely SNPs, in a region that can capture common genetic variation. Efficiency and power are improved if a set of haplotype tagging SNPs (ht-SNPs) are chosen on the basis of detailed knowledge of the haplotype patterns across a locus of interest. In the process, we have created a database of known genetic single nucleotide polymorphisms (SNPs) in immunologically relevant genes in order to utilize existing SNPs for pathway-based association studies. The long-range goal of genetic association studies is to identify potential genotypic differences that may bear important predictive value for infectious complications of disease (and perhaps other therapy related toxicities). Moreover, we are also heavily invested in studies designed to identify genetic variants in genes of immune function and telomere stability that are associated with susceptibility to pediatric acute lymphoblastic leukemia and lymphomas. The same strategy has also been extended to pilot studies in solid tumors, such as osteogenic sarcoma, colorectal and prostate cancer. The role of inflammation in cancer can be studied in genetic association studies. For instance, we have recently shown that variants in the IL8 gene, which alter expression of this chemokine which is a potent attractant for neutrophils, can alter the risk for gastric cancer. This supports the observation that chronic inflammation contributes to the carcinogenesis of gastric cancer, both in response to Helicobacter pylori infection and independent of infection status. We have identified a variant allele of the FCGR3A which contributes to the development of Kaposi Sarcoma (KS) in HIV-infected men. The V allele of the FCGR3A gene is strongly associated with KS and influences the likelihood of developing infection with KSHV, an important co-factor for KS. Parallel studies in classical KS- namely KS in non-HIV infected individuals in the Mediterranean Basin- have shown a role for genetic variants in these two genes, FCGR3A and IL8 in determining the risk for KS. The laboratory has integrated a series of programs and approaches in population genetics, epidemiology and molecular evolution, which assist in the choice and analysis of genetic variants under study. Adaptation and integration of new informatic tools, such as Genewindow (http://genewindow.nci.nih.gov) and ht-SNP selection according to the Stram algorithm have also been implemented. Comparison of sequence analysis across species, focused on SNPs and haplotypes is a powerful tool to identify a priori, possible functional variants and serves as the basis for targeting regions for SNPs analysis. The laboratory is closely related to two programs in the NCI, the Core Genotyping Facility of the NCI (http://cgf.nci.nih.gov) and the SNP500cancer program (http://snp500cancer.nci.nih.gov) of the Cancer Genome Anatomy Project (http://cgap.nci.nih.gov), both run by this PI. The availability of high throughput sequence and genotype expertise is critical for conducting pilot studies as well as sufficiently powered, well-designed studies in molecular epidemiology and pharmacogenomics. We have developed a series of collaborations with leading epidemiologists and bio-statisticians in the Division of Cancer Epidemiology and Genetics (DCEG). Collaborative efforts have resulted in the development of new approaches to assess the false positive report probability (FPRP), a new tool intended to better assess the robustness of findings in genetic association studies. Lastly, the long-term goals of the laboratory are to identify and characterize genetic variants that could be used as prospective tools for early detection and intervention as part of the shift towards 'personalized' medicine. At the same time, the current strategy should continue to highlight genetic variants in key pathways in cancer susceptibility and outcome.
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