In a recent study published in the British Journal of Haematology, researchers analyzed inheritance patterns of multiple myeloma (MM) to better understand the disease’s etiology.1
Eleven case-controlled studies across Europe, Canada and the United States were pooled via the International Multiple Myeloma Consortium, using data from 2843 cases and 11,470 healthy controls. The presence of a family member with history of any lymphohematopoietic (LH) cancer was associated with risk of developing MM. LH cancer was defined as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, leukemia, MM and monoclonal gammopathy of undetermined significance, the pre-malignant form of MM.
The association increases when a first-degree relative has a history of LH cancer, particularly MM, and when more than 1 family member has a history of LH cancer. The association is more significant if the relative is female, particularly a sister. Men had the highest risk of developing MM, particularly those of African American descent. The observations echoed those of previous investigations, though with greater statistical power and reliable subgroup stratification.
The authors provided compelling genetic support for their data, noting increased expression of hyperphosphorylated paratarg-7 protein in African American patients with MM (an autosomal dominant, inherited risk factor). Genome-wide association studies (GWAS) also support disease heritability, showing higher mortality rates for patients with MM who carry single nucleotide polymorphisms (SNPs) at chromosome 16p13. SNP is close to the FOPNL gene, increased expression of which is associated with poor prognosis in MM patients.2
Other SNPs have also been associated with MM, yet GWAS studies are alone unable to determine causality and heritability. The attribution of SNPs to associative genes are often made using proximity alone.3 Integration of genetic and clinical data illuminates causal variants, an essential step in the development of targeted treatments and for effective screening programs.
Although familial clustering suggests disease heritability, shared non-genetic risk factors, such as environmental exposures, cannot be ignored. This is also relevant to the effect modification observed for African American men, as the associated data was taken exclusively from studies conducted in the United States. In an interview with Cancer Therapy Advisor, Leah Schinasi, PhD, a post-doctorate fellow of in the Department of Environmental Health and Occupation at Drexel University in Philadelphia, Pennsylvania, noted, “the results from our work provide compelling evidence to support the hypothesis that MM is heritable. An important way to build upon this work would be to design and conduct a study of gene-environment interactions in relation to MM. Such a study might help to explain why some people are more or less susceptible to MM as a result of environmental exposures.”
Results to date are encouraging. Oncologists may be on the path towards elucidating clinically translatable etiologies of MM. Dr Schinasi and her colleagues are investigating the relationship between pesticide exposure and risk of developing MM. Other researchers have indicated up to 2 times the risk of developing MM for men exposed to the pesticides carbaryl, captan and DDT.4
Should these results be confirmed, and additional subpopulations demonstrate an increased risk of developing MM, oncologists will be provided with a narrower focus for future gene-environment interaction studies.
- Schinasi LH, Brown EE, Camp NJ, et al. Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium. Br J Haematol. 22 Jun 2016. doi: 10.1111/bjh.14199 [Epub ahead of print]
- Ziv E, Dean E, Hu E, et al. Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. Nat Commun. 22 Jul 2015. doi:10.1038/ncomms8539 [Epub ahead of print]
- Zhang J, Jiang K, Lv L, et al. Use of genome-wide association studies for cancer research and drug repositioning. PLoS ONE 10(3): e0116477. doi:10.1371/journal.pone.0116477
- Presutti R, Harris SA, Kachuri L, et al. Pesticide exposures and the risk of multiple myeloma in men: an analysis of the North American Pooled Project (NAPP). 4 Jun 2016. Int J Cancer. doi: 10.1002/ijc.30218 [Epub ahead of print]