Variants of MBL2 Gene Associated with Colon Cancer Risk in African Americans
Age-adjusted incidence rates for colon cancer by race/ethnicity, all ages, both sexes 2000-2008. Statistical data available from the NCI Surveillance, Epidemiology, and End Results (SEER) Program website (http://seer.cancer.gov/).
Evidence from a case-control study suggests that certain genetic alterations of a protein that inhibits inflammation are associated with increased susceptibility to colon cancer in African Americans.
Curtis C. Harris, M.D., chief of CCR’s Laboratory of Human Carcinogenesis, and colleagues from CCR and other NCI divisions examined the role of genetic variants of mannose-binding lectin 2 (MBL2), a protein that is instrumental in immunity and acts as an inflammatory mediator, in colon cancer susceptibility. Since recent research findings have suggested an association between MBL2 variations and other cancers, the NCI-led research team hypothesized that MBL2 may also be a factor in colon cancer risk.
The MBL2 gene codes for the plasma glycoprotein MBL, which is a molecule of the innate immune system. MBL binds to sugars on pathogens, ultimately leading to the pathogens’ destruction. Approximately five percent of the population has an MBL deficiency, which predisposes individuals to bacterial, viral, and fungal infections, which often cause inflammation. Chronic intestinal inflammation and inflammatory bowel diseases are risk factors for colon cancer and colon neoplasia.
To conduct their analysis, the researchers used samples from The NCI-Maryland Colon Cancer Case-Control Study. The study population is made up of African Americans and Caucasians and includes 261 colon cancer patients and 537 individuals without cancer.
The research team examined 24 genetic variants, or single nucleotide polymorphisms (SNPs), of MBL2. Among the MBL2 SNPs analyzed, four common variants located on a particular section of the gene known as 3’-UTR were found. Further analysis showed that these particular sets of SNPs, or haplotypes, are associated with increased risk of colon cancer in African Americans.
The researchers also observed that the African American patients with colon cancer had lower MBL plasma levels, which may account in part for the increased risk associated with colon cancer in African Americans carrying specific MBL2 haplotypes.
The team conducted a functional analysis of microRNA (miRNA) binding on MBL levels and activity. The binding of miRNAs, which regulate gene expression, to messenger RNAs (mRNAs) has been shown to reduce protein translation. Results of the analysis showed that miRNA binding in one of the MBL2 alleles was associated with lower MBL plasma levels and activity. MBL serum levels were also analyzed, and certain haplotypes known to correlate with moderate to low MBL serum levels showed an association with increased risk of colon cancer in African Americans.
The scientists only observed evidence for increased susceptibility to colon cancer – frequency of specific MBL2 haplotypes and lower MBL levels – in African Americans; similar variations were not observed in Caucasians in the study.Summary Posted: 03/2012
Zanetti KA, Haznadar M, Welsh JA, Robles AI, Ryan BM, McClary AC, Bowman ED, Goodman JE, Bernig T, Chanock SJ, Harris CC. 3'-UTR and Functional Secretor Haplotypes in Mannose-Binding Lectin 2 Are Associated with Increased Colon Cancer Risk in African Americans. Cancer Res. 2012 Mar 15 PubMed Link