Abstract
Genetic variations in the hyaluronan synthase 1 gene (HAS1) influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM). We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS), 72 with Waldenstrom macroglobulinemia (WM), 169 with chronic lymphocytic leukemia (CLL), as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP) in HAS1 intron3 are significantly associated with B-cell malignancies (range p = 0.007 to p = 10−5), but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p = 0.005, Odds Ratio = 5.8 (OR)), a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR = 1.78), but not for sporadic MGUS or for breast cancer (OR<1.0). The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B-cell malignancies but not for solid tumors.
Highlights
Hyaluronan synthase 1 (HAS1) produces hyaluronan (HA), a polysaccharide with complex biological effects [1]
When MM, chronic lymphocytic leukemia (CLL) and Waldenstrom macroglobulinemia (WM) were evaluated as a single group in comparison with the healthy control group, we found a significant association between the linked HAS1 intron3 single nucleotide polymorphisms (SNP), and the risk of systemic B-cell malignancy
By sequencing in 832 patients and 582 healthy controls a segment of the HAS1 gene known to influence aberrant HAS1 splicing [7;8], we show that the presence of HAS1 SNPs is strongly associated with the diagnosis of a systemic B-cell malignancy, but not with a solid tumor
Summary
Hyaluronan synthase 1 (HAS1) produces hyaluronan (HA), a polysaccharide with complex biological effects [1]. We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 832 patients and 582 controls. A major strength of this study is that we have analyzed the HAS1 polymorphisms in five different disease cohorts and two geographically independent populations (western Canadians and the Icelandic kindred) with their appropriate healthy donor control groups. This is the first report that risk for B-cell malignancies and an inherited monoclonal gammopathy-prone phenotype is directly correlated with intronic HAS1 SNPs, likely by promoting aberrant HAS1 splicing
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