INTRODUCTION: Lobular carcinoma in situ (LCIS) has been accepted as a marker of risk for the development of invasive breast cancer, yet modern models of breast carcinogenesis include LCIS as a precursor of low-grade carcinomas. We provide evidence favoring a clonal origin for LCIS and synchronous estrogen receptor-positive malignant lesions of the ductal and lobular phenotype. METHODS: Patients with prior LCIS undergoing mastectomy were identified preoperatively from 2003-2008. Specimens were widely sampled, and frozen blocks were screened for LCIS and co-existing malignant lesions, and subject to microdissection. Samples from 65 patients were hybridized to the Affymetrix SNP 6.0 array platform. Cases with both an LCIS sample and an associated ductal carcinoma in situ (DCIS) or invasive tumor sample were evaluated for patterns of somatic copy number changes to assess evidence of clonal relatedness. RESULTS: LCIS was identified in 44 of the cases, and among these, a DCIS and/or invasive lesion was also identified in 21 cases. A total of 17 tumor pairs had adequate DNA/array data for analysis, including 9 pairs of LCIS/invasive lobular cancer (ILC), 4 pairs of LCIS/DCIS, and 4 LCIS/invasive ductal cancer (IDC). Overall, 7 pairs (41%) were judged to be clonally related; in 5 (29%), evidence suggested clonality but was equivocal, and 5 (29%) were considered independent. Clonal pairs were observed with all matched lesion types and low and high histological grades. We also show anecdotal evidence of clonality between a patient-matched triplet of LCIS, DCIS, and IDC. CONCLUSIONS: Our results support the role of LCIS as a precursor in the development of both high- and low-grade ductal and lobular cancers.