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Characterization of environmental and genetic factors in multiple-case lymphoid cancer families Jones, Samantha Jean

Abstract

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.

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