Primary lymphoma of the breast accounts for <2% of extranodal non-Hodgkin’s lymphoma and generally displays morphology consistent with diffuse large B-cell lymphoma (DLBCL). The pathogenesis and histogenesis of primary breast lymphoma are currently unknown and represented the aim of this study. Thirteen cases of primary breast lymphoma (all DLBCL) were analyzed for physiological somatic hypermutation (SHM) of IgV and BCL-6 genes, as well as for aberrant SHM of PAX-5, PIM-1, RhoH/TTF and c-MYC genes. A functional IgVH rearrangement was identified in 8/13 (61.5%) primary breast lymphomas. All IgVH genes displayed SHM, with a mutation frequency ranging from 4.0% to 25.9%, suggesing that primary breast lymphomas derive from GC-related B-cells. The IgVH gene families utilized included VH4 (4/8 cases), VH3 (3/8 cases) and VH2 (1/8 case). Three cases utilized the same VH 4.30.1/4-31 gene. Mutations of BCL-6 were detected in 7/13 (53.8%) cases, further confirming the finding that primary lymphomas of the breast derive from GC-experienced B cells. Analysis of aberrant SHM of proto-oncogenes was performed on selected regions known to contain >90% of mutations found in lymphoma. Overall, mutations in at least one of the four proto-oncogenes targeted by aberrant SHM were found in 9/13 (69%) primary breast lymphomas, whereas mutations in more than one gene were found in 4/9 (44%) cases. Each of the four proto-oncogenes was altered in a significant fraction of primary breast lymphomas (PAX-5 in 4/9 cases; RhoH/TTF in 5/9 cases; PIM-1 in 5/9 cases and c-MYC in 2/9 cases). The overwhelming majority of mutations was represented by single base-pair substitutions (n=36), whereas in only one instance a deletion of a short DNA stretch was observed. Among the 36 single base-pair substitutions detected in primary breast lymphoma, the transition/transversion ratio was 1.76 (expected 0.5; p<0.01; Chi square test), reflecting the mutational profile seen in nodal DLBCL of immunocompetent hosts. In PIM-1, a fraction of mutations led to amino acid substitution, with potential functional consequences. In particular, three primary breast lymphomas displayed four missense mutations localized within the serine-threonine kinase domain of PIM-1. The association of primary breast lymphoma with aberrant SHM of proto-oncogenes expands the types of aggressive lymphomas marked by this molecular abnormality and provides clues for understanding breast lymphoma pathogenesis. In particular, missense mutations in the PIM-1 coding region can deregulate its function, whereas mutations of the 5′ regulatory regions of PAX-5, RhoH/TTF and c-MYC are expected to influence the expression and regulation of these genes in a fashion similar to that reported for the BCL-6 gene in B-cell lymphoma. Consistent with the role of PAX-5 in B-cell differentiation, of RhoH/TTF in signal transduction, and of c-MYC in B-cell growth and fate, deregulation of these genes by aberrant hypermutation may contribute to breast lymphoma pathogenesis by multiple pathways.