The goal of the laboratory is to investigate the genetic basis of cancer and its outcomes. The major focus of the laboratory is on annotating and applying common genetic variation in candidate genes in key pathways in innate immunity and cancer biology, such as telomere stability. We have incorporated current approaches to identify and validate the most common form of germ-line genetic variation, the single nucleotide polymorphism (SNP). We have transitioned from the analysis of functional variants by the direct approach, which was limited by our knowledge of function, to a more efficient indirect approach. The latter seeks to comprehensively analyze common variants across a locus in an effort to determine genetic markers. Our strategies include using haplotype-tagging SNPs and the greedy algorithm for tag SNPs in well-conducted molecular epidemiology studies in cancer. Annotation of common germ-line variation in the human genome has substantially accelerated the investigation of the genetics of cancer etiology and cancer outcomes. Initially, linkage analysis in families with an inordinately high rate of cancer uncovered genes with high penetrance (e.g., BRCA1/BRCA2 in breast and ovarian cancer, APC in colon cancer with adenomatous polyposis coli and CDNK2A in melanoma). Although these notable examples provided evidence that germ-line genetic variation can contribute to cancer risk, these are rare mutations, accounting for only a small portion of breast or colon cancer in the general population. Recently, the search has turned to common genetic variants that alter risk for common (e.g., breast, prostate, colon cancers) and more recently, the less common cancers of childhood. In part, the strategy emerges from a clearer understanding of cancer as a complex multistage disease. Indeed, preliminary evidence indicates that sets of common variants are likely to contribute to common, complex diseases, such as cancer or diabetes. Finally, comprehensive annotation of common genetic variation across the human genome opens up a new range of opportunities to search in depth. Consequently, there has been a shift from family linkage studies to association studies conducted in population-based studies, with unrelated subjects. To date, the findings that have replicated in cancer appear to be variants with moderate to small effect (odds ratios between 1.3 and 2.0). Thus, it is likely that many common variants could contribute to the development of cancer. Common genetic variants are of high interest for susceptibility and protection to cancer, which could soon have public health significance for screening and for patterns of care. For example, variants have been shown to influence outcome in other diseases, such as survival or risk for infection and other treatment-related complications, such as pharmacogenomics. Although there are a few notable examples that have unequivocally been established in cancer, the recent changes in genomics, public databases and genotyping platforms offer great promise that many more will be found. We are committed to investigate the hypothesis that common genetic variants contribute to the risk for cancer and its outcomes. Furthermore, it plausible that genetic variation could influence more than one type of cancer or outcome. On the other hand, distinct variants could be associated with a particular cancer or subtype. To achieve this aim, we have forged a series of collaborations with molecular epidemiologists in the intramural and extramural communities to conduct a sequence of studies to confirm significant variants. We are committed to continue to utilize state-of-the-art tools for genotyping and genetic analysis as well as the public databases to conduct high quality candidate gene/pathway studies in hematopoietic malignancies and pediatric bone cancers. The laboratory has developed a specialized program dedicated to the characterization of common (minor allele frequency greater than 5%) and less common (minor allele frequency between 1 and 5%) in genes in three categories: 1. regulatory or innate immune genes (e.g., cytokines, interleukins and C-type collectins); 2. telomere stability genes; and 3. the TP53 pathway. Our efforts have focused on defining patterns of only serve as informative surrogate markers for analysis but improve the prospects for characterizing one or more causal SNPs. Our recent publications have established a strong track record in populations genetics and we will continue to look at patterns of variation for sets of genes and in genes of high interest (such as immune genes like MBL2 or the Vitamin C transporters). In these studies, we have examined the pattern of variation across populations and characterized haplotype structure for genes in particular pathways to be applied in molecular epidemiology studies. Notably, we have deliberately sought collaborations to pursue functional consequences of significant SNPs so that we are not diverted from the specific aims below. The laboratory will continue to concentrate the majority of its resources to effectively conduct new studies and at the same time, re-evaluate how to improve our efficiency and capacity. This will require a continued investment in the assessment of technical and bio-informatic issues that can accelerate the pace of analysis. My scientific leadership role as director of the Core Genotyping Facility (CGF)(http://cgf.nci.nih.gov), the SNP500Cancer program (http://snp500cancer.nci.nih.gov) and co-director of the Cancer Genetic Markers of Susceptibility (CGEMS)(http://cgems.cancer.gov) provides excellent opportunities to access expertise in methodological and statistical analysis of complex diseases as well as access to new technical platforms. The long-term goal is to participate in the conduct of whole genome scans in the priority diseases currently the focus of my laboratory, hematopoietic malignancies (adult NHL and pediatric acute leukemias) and pediatric bone tumors. Currently, I am leading efforts in whole genome scans for breast and prostate cancer, diseases for which there are a large number of cases and controls derived from well-executed, existing studies with environmental exposure data. The success of CGEMS should establish a strong foundation for pursuing well-designed and sufficiently powered studies in hematopoietic malignancies and pediatric bone tumors, when and if sufficient samples are available. It is important to recognize that large candidate gene studies as well as whole genome scans are discovery tools that can localize regions of high interest. As such, it will be necessary to finely map significant variants by genetic and functional studies. In this regard, my laboratory is committed to following up promising markers by conducting dense genotype analysis combined with re-sequence analysis and population genetics. Lastly, it is anticipated that we will further integrate genetics into the diagnosis, treatment decisions and ultimately prevention of cancer
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