KANK1 associated with higher risk for multiple myeloma among African Americans
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ORLANDO — Expression of the KANK1 gene appeared associated with higher risk for multiple myeloma among African Americans, according to results of the case-control African American Multiple Myeloma Study presented at ASH Annual Meeting and Exposition.
The study also showed that African Americans had more than two times the heritability for multiple myeloma than individuals of European ancestry, and that variations in white blood cell counts had little role in this heritability when comparing the two groups.
“African Americans have about two times higher risk [for] multiple myeloma compared with whites, and we still don’t know why. So, we launched a large study to look a genetic risk factors, hoping we would find some giant signal the way we did with prostate cancer,” senior author Wendy Cozen, DO, MPH, professor of preventive medicine and pathology and director of the population-based pathology core at Keck School of Medicine of USC, told Healio.
The key takeaway is that further study is needed, according to Cozen.
“It’s still inconclusive whether white blood cell traits are a risk factor in multiple myeloma; however, using a gene expression profile, we did find one signal — called KANK1 — in which patients who expressed this gene had a significantly higher risk [for] multiple myeloma among African Americans,” Cozen said.
Her research group did not enter the study with a hypothesis about which genes may predict a higher risk for multiple myeloma among African Americans. Instead, they examined all genes to see what “fell out,” she said. “Now we must conduct functional studies to see why expression of this gene may be a risk factor for multiple myeloma.”
Higher expression of KANK1 also has been observed among African Americans with renal cell carcinoma, which is another type of cancer that disproportionately affects African Americans, Cozen explained.
The study included 1,813 African American patients with multiple myeloma and 8,871 cancer-free controls at 12 different sites across the U.S. Cozen and colleagues examined blood cell traits, including white blood cell count and subsets such as lymphocytes, neutrophils, monocytes and basophils, to see if they predicted multiple myeloma risk among African Americans. Additionally, they studied whether the genes, assessed by imputation, were risk factors for multiple myeloma.
The investigators used previously developed genetic instruments for white blood cell phenotypes in the UK Biobank to identify white blood cell predictors of multiple myeloma heritability. They also used published germline genetic prediction models of gene expression in African Americans based on regularized regression. The investigators obtained genetic variation data from DNA from patients analyzed on a chip, Cozen explained, and then compared it with similar data from African American control subjects.
“This is the largest study of multiple myeloma in African Americans in the world,” Cozen said.
The combination of multiple myeloma being a rare cancer and the difficulty of collecting enough samples in this minority population resulted in nearly a decade to yield these results, she added.
The researchers found that heritability of multiple myeloma captured by common genetic variants appeared higher among African Americans (33%) than individuals with European ancestry (16%).
Cozen and colleagues examined 2,727 genes through a transcriptome-wide association study and found increased expression of KANK1 to be positively associated with multiple myeloma (P = 1 ×10-5; R2 = .237). Higher expression of DNAJC27 also appeared associated with multiple myeloma (P = 1.6 × 10-5; R2 = .246), but not nearly as strongly as the relationship seen with KANK1.
The researchers found no association between white blood cell genetic determinants and multiple myeloma risk among African Americans.
“It’s too early for the results of this study to have an impact on clinical practice,” Cozen told Healio.
There are two goals in finding genetic risk factors, she explained.
“First, if we can find a signature in patients (a particular genetic profile), then we can screen them for risk,” she said. “There is a benign precursor for multiple myeloma called monoclonal gammopathy of undetermined significance (MGUS), but only 1% per year progress to multiple myeloma. If we could develop another screening tool for multiple myeloma, then we would know which MGUS patients to follow for progression.
“The other goal is that if KANK1 ends up having some meaning in the genesis of multiple myeloma, then maybe it will lead to a drug target sometime down the road,” she added. – by Drew Amorosi
Reference:
Kachuri L, et al. Abstract 4379. Presented at: ASH Annual Meeting and Exposition; Dec 7-10, 2019; Orlando.
Disclosures: Cozen reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.