Population-based Genetics of Non-Hodgkin Lymphoma
The focus of this research is to discover the inherited genetic factors that influence susceptibility to Non-Hodkin Lymphoma and other related Lymphoid Cancers within families.
|Project Leaders||Angela Brooks-Wilson|
|Project Co-Investigators||Joseph Connors , Randy Gascoyne , John J. Spinelli|
Canada's Michael Smith Genome Science Centre
British Columbia Cancer Agency
Simon Fraser University
Canadian Institutes of Health Research
Example family tree with Lymphoid cancers indicated as solid shading.
Cancer is now responsible for 1 million potential years of life lost in Canada, and costs Canadians 14.2 billion dollars/year in direct and indirect costs. The incidence of non-Hodgkin lymphoma (NHL) has nearly doubled in the last 35 years, and it is now the 5th most common malignancy in Canada. NHL cases likely arise in a genetically susceptible part of the population, potentially in individuals who have faulty DNA repair mechanisms. Methods to prevent and avoid NHL and other cancers, for example by means of screening for at-risk individuals, will be of increasing importance for the Canadian healthcare system.
Programmed cell death, or apoptosis, is a natural mechanism used to remove damaged cells from the body before they can become cancerous. This process of detection and repair of DNA damage carried out by our bodies is intimately connected with the cellular controls that trigger apoptosis. If cells that sustain DNA damage fail to undergo apoptosis, they may incur additional mutations that take them along the road to becoming cancerous. Non-Hodgkin lymphoma (NHL) includes a group of tumours of immune cells. They have in common a tendency to show a type of DNA damage called a translocation, in which two chromosomes become abnormally fused together. Translocations are generally found next to specific genes related to development of lymphoma, and result in altered gene expression and aberrant lymphoid cell growth. We reason that two types of failure are likely to have happened in such cells: 1) failure to repair DNA damage properly, and 2) failure to flag the cell as damaged and trigger apoptosis. Previously, we studied the relationship between genetic variation in six key DNA repair genes and NHL. In this work, we will focus on one DNA repair gene we found to be associated with NHL, and will also assess whether genetic variation in any of 15 apoptosis genes contributes to NHL risk. We will be working with an international consortium for lymphoma research to further confirm our findings. The identification of genetic factors that predispose individuals to NHL may be useful in the development of diagnostic tests to help identify those at-risk for this cancer, leading to early diagnosis and treatment, as well as the identification of new drugs.
- Schuetz JM, Daley D, Leach S, Conde L, Berry BR, Gallagher RP, Connors JM, Gascoyne RD, Bracci PM, Skibola CF, Spinelli JJ and AR Brooks-Wilson. Non-Hodgkin lymphoma risk and variants in genes controlling lymphocyte development. PLoS ONE 2013; 8(9):e75170.
- Bretherick KL, Schuetz JM, Morton LM, Purdue MP, Conde L, Gallagher RP, Connors JM, Gascoyne RD, Berry BR, Armstrong B, Kricker A, Vajdic CM, Grulich A, Hjalgrim H, Smedby KE, Skibola CF, Rothman N, Spinelli JJ and AR Brooks-Wilson. Sex- and subtype-specific analysis of HAFX polymorphisms in non-Hodgkin lymphoma. PLoS ONE. 2013; 8(9):e74619. PMID: 24069324. PMCID: PMC3775730.
- Bretherick KL, Leach S and AR Brooks-Wilson. Functional characterization of genetic polymorphisms in the H2AFX distal promoter. Mutation Research 2014 Aug-Sept; 766-767:37-43.
- Morton LM, Slager SL, Cerhan JR, Wang SS, Vajdic CM, Skibola CF, Bracci PM, de Sanjosé S, Smedby KE, Chiu BC, Zhang Y, Mbulaiteye SM, Monnereau A, Turner JJ, Clavel J, Adami HO, Chang ET, Glimelius B, Hjalgrim H, Melbye M, Crosignani P, di Lollo S, Miligi L, Nanni O, Ramazzotti V, Rodella S, Costantini AS, Stagnaro E, Tumino R, Vindigni C, Vineis P, Becker N, Benavente Y, Boffetta P, Brennan P, Cocco P, Foretova L, Maynadié M, Nieters A, Staines A, Colt JS, Cozen W, Davis S, de Roos AJ, Hartge P, Rothman N, Severson RK, Holly EA, Call TG, Feldman AL, Habermann TM, Liebow M, Blair A, Cantor KP, Kane EV, Lightfoot T, Roman E, Smith A, Brooks-Wilson A, Connors JM, Gascoyne RD, Spinelli JJ, Armstrong BK, Kricker A, Holford TR, Lan Q, Zheng T, Orsi L, Dal Maso L, Franceschi S, La Vecchia C, Negri E, Serraino D, Bernstein L, Levine A, Friedberg JW, Kelly JL, Berndt SI, Birmann BM, Clarke CA, Flowers CR, Foran JM, Kadin ME, Paltiel O, Weisenburger DD, Linet MS, Sampson JN. Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014 Aug;2014(48):130-44. doi: 10.1093/jncimonographs/lgu013. PMID:25174034.
- Krajden M, Yu A, Braybrook H, Lai AS, Mak A, Chow R, Cook D, Tellier R, Petric M, Gascoyne RD, Connors JM, Brooks-Wilson AR, Gallagher RP, Spinelli JJ. GBV-C/hepatitis G virus infection and non-hodgkin lymphoma: A case control study. Int J Cancer. 2009 Nov 10. [Epub ahead of print]
For all project related inquires please contact us.
Stephanie McInnis, Project Coordinator
Genome Sciences Centre, BC Cancer Agency
Phone: 604-675-8000 ext. 7965