The genetic factors that lead to WM are mostly unknown but are likely to involve inherited polymorphisms that might be markers of increased risk for developing WM, and somatic mutations that might be acquired during the events leading to oncogenesis and cancer progression. By intensive sequencing of the hyaluronan synthase 1 (HAS1) gene in malignant and normal cells from patients with WM, we have identified both types of mutation in HAS1 exons and introns. Acquired HAS1 mutations are found in malignant cells as well as presumptively nonmalignant CD34+ progenitor cells. This suggests that acquired HAS1 mutations precede frank malignancy and might contribute to the initial transforming events in WM as well as to disease progression.