title: Inherited polymorphisms in hyaluronan synthase 1 predict risk of systemic B-cell malignancies but not of breast cancer.
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.
authors.affiliation: University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Hemalatha
authors.initials: H
authors.lastname: Kuppusamy
authors.affiliation: University of Iceland, Reykjavik, Iceland.
authors.forename: Helga M
authors.initials: HM
authors.lastname: Ogmundsdottir
authors.affiliation: University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Baigorri
authors.affiliation: University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Warkentin
authors.affiliation: Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Hlif
authors.initials: H
authors.lastname: Steingrimsdottir
authors.affiliation: Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: Vilhelmina
authors.initials: V
authors.lastname: Haraldsdottir
authors.affiliation: University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mant
authors.affiliation: University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Mackey
authors.affiliation: Dept. of Hematology, Cancer Care Manitoba and the University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Johnston
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.affiliation: University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Belch
authors.affiliation: University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Pilarski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000076002:Hyaluronan Synthases; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010265:Paraproteinemias / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000473:pathology
chemical_list: D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; D000076002:Hyaluronan Synthases