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Genetics of healthy aging. Genetics of lymphoid cancers in families.
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - Nov 2020)
Lymphoid cancers, the fifth most common cancer type in Canada, comprise a clinically and biologically heterogeneous group of neoplasms. Established risk factors include older age, male sex, compromised immune function, and family history of lymphoproliferative disorders. The hygiene hypothesis, according to which a relative lack of infectious exposure during early childhood may cause aberrant immune development and subsequent adult-onset immune-related diseases, including allergies, autoimmune conditions and some lymphoid cancers, provides a framework for understanding these risk factors. Susceptibility genes involved in immune function and DNA repair have been identified; however, there remains a large gap in our knowledge of genetic and environmental factors for familial lymphoid cancers.We examined familial aggregation, age of onset and environmental factors in more than 200 multiple-case lymphoid cancer families. Familial lymphoid cancer ages of onset were substantially earlier than comparable population data and showed an anticipation effect after controlling for ascertainment biases. Relative to the general population, families were enriched for some combinations of lymphoid cancers (e.g., HL/HL, CLL/CLL). Familial cases were more likely to have allergies and a tonsillectomy, which may indicate defective immune regulation. The risk of lymphoma tended to decrease with later birth order and larger sibship sizes. Measures of family structure and crowding relate to the hygiene hypothesis as they affect age and extent of exposures to infections, with low birth order and smaller sibships correlating with higher risk. These associations underscore the complex etiology of familial lymphoma and suggest that lymphoid cancers in multiple-case families may be different from sporadic cases.Genome-wide scans have identified few risk alleles with small effect sizes in multiple-case families. We performed a genome-wide Identity-by-Descent analysis using 1.8 million markers on a well-characterized multi-generational family with 4 lymphoid cancer cases. Three interesting candidate variants were found (MYC, EPHA1, MMS19), but no compelling high-penetrance disease variant segregated with lymphoid cancer. Identifying genetic factors in rare lymphoid cancer families will aid in uncovering key networks involved in cancer susceptibility. Lymphoma has an important familial component. Establishing genetic and environmental associations facilitates a better understanding of lymphomagenic mechanisms and effective approaches to cancer prevention and clinical management.
Background. Epithelial ovarian cancer (EOC) and age of natural menopause (ANM) are two complex traits impacting women’s health. ANM is also an important EOC risk factor. Insight into genetic factors influencing EOC and ANM could provide novel entry points for understanding EOC pathogenesis, and the normal process of ovarian aging. Methods. A two-stage genome-wide association study (GWAS) design using DNA pooling in Stage 1 was used to discover single nucleotide polymorphisms (SNPs) associated with histology-specific EOC risk, and population-specific variation in ANM. SNP-trait associations discovered in Stage 1 of these GWAS were replicated in two different consortia; EOC association in the Ovarian Cancer Association Consortium (OCAC), and ANM associations in the ReproGen Consortium. Results. Eight subtype-specific SNP-EOC associations discovery in Stage 1 of the EOC GWAS were replicated (unadjusted P
Background. Non-Hodgkin lymphomas (NHL) form a heterogeneous group of lymphocyte-derived solid tumors. Poor control of development and cell death in lymphocytes can lead to autoimmune disease, cancer and drug resistance. Lymphocyte development is a complex process marked by intense competition for nutrients, necessary DNA breaks and fast division times. BCL2, which controls apoptosis in lymphocytes, can be deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation and gene amplification.Methods. I surveyed genetic variation in 21 genes with roles in programmed cell death, lymphocyte development and DNA repair in constitutional DNA of NHL patients by gene re-sequencing. Genetic association tests for susceptibility to NHL subtypes were then conducted in a population-based collection of 797 NHL cases and 790 controls. I further studied BCL2 mutations in 491 tumors to investigate somatic mechanisms underlying lymphomagenesis.Results. 269 SNPs were discovered in constitutional DNA, 61% of which were novel. A few variants showed association with an NHL subtype, but most were not significant after correction for multiple tests. One variant near miR-155 was associated with marginal zone lymphoma (MZL). BCL2 is mutated in 60% of germinal centre B-cell like (GCB) DLBCL and in 85% of follicular lymphoma (FL); both arise from germinal centre B-cells and are characterized by t(14;18). The decreasing number of mutations with distance from the promoter and the enrichment of transitions over transversions imply that these mutations arise by somatic hypermutation. Many mutations are non-synonymous, and are rarely found in regions encoding BH domains. Other NHL subtypes, typically without t(14;18) and from different stages of development and lineages, showed very low levels of BCL2 mutations. 26% of DLBCL cases without detectable t(14;18) contained BCL2 mutations, indicating that mutations also occur by other mechanisms.Conclusions. These results strongly suggest that t(14;18) is important for acquiring additional BCL2 mutations in GCB-DLBCL and FL. The prevalence and the high number of mutations per sample suggest a selective advantage of BCL2 mutants in tumor development. Rs928883, near miR-155, is associated with increased risk of MZL. This is the first reported association between a miRNA-locus germline polymorphism and a subtype of non-Hodgkin lymphoma.
Introduction: Gastric and esophageal cancers are among the deadliest forms of cancer. Studies of human cancer susceptibility examine factors associated with the incidence of disease. Studies of human cancer prognosis and prediction examine factors associated with disease outcomes. This dissertation is about molecular and other factors that affect survival of gastric and esophageal cancer patients. Methods: Population-based registry data linked with patient outcome data was used to describe the epidemiology of gastric and esophageal cancers in BC; to compare survival of cancer patients in BC, and Ardabil, Iran and to describe differences in survival of BC patients of different ethnicity. The ethnicity of patients was determined based on lists of names corresponding to each ethnic group. A prospective cohort study was conducted to examine the effect of genetic polymorphisms in TIMP (1-4) and MMP (2, 7 and 9) genes. Results: Analysis of cancer registry data points to several factors associated with gastric and esophageal cancer survival. Patients with gastric cardia experience worse survival compared to other gastric cancers. Ethnicity of gastric and esophageal cancer patients is associated with their survival. Gastric and esophageal cancer patients diagnosed in British Columbia have better survival compared to those daignosed in Adabil, Iran. Genetic polymorphisms are also associated with survival. My prospective study identified 4 genetic polymorphisms at TIMP-3 associated with survival of esophageal adenocarcinoma and gastroesophageal junction (GEJ). Conclusion: Besides established prognostic indicators, other factors affect survival of gastric and esophageal cancers. Differences in survival by ethnicity support the importance of ethnicity as a prognostic factor. Survival differences between BC and Ardabil are likely due to disease characteristics and patient factors, in addition to differences in healthcare systems. TIMP3 genetic polymorphisms are promising prognostic factors for adenocarcinoma of esophagus and GEJ. Modeling prognosis based on host factors, including ethnicity and genetic polymorphisms, is an emerging field of translational cancer research. More research is needed to fully explore the functional effects of TIMP3 polymorphisms, and to identify both genetic and lifestyle factors underlying the effect ethnicity on survival.