Clonality analysis of multifocal ipsilateral breast carcinomas using X-chromosome inactivation patterns

Abstract

The definition of multifocal breast cancer is ambiguous, and its incidence varies depending on the definition and detection methods. Multifocal breast cancers either have the same clonal origin or arise from completely distinct progenitor cells. The current American Joint Committee on Cancer Staging system and College of American Pathologists breast tumor guidelines state that only the largest tumor needs to be staged and studied immunohistochemically, on the assumption that they are of the same origin. However, some multifocal tumors have been proved to have arisen from different clones. In the present study, 71 cases of surgically resected multifocal breast cancers were selected. To detect and characterize the tumors of each clonal origin, a human androgen receptor gene (HUMARA) assay to compare the X-chromosome inactivation patterns of multiple tumors was conducted. Twenty-nine of 71 (40.8%) patients were revealed to be heterozygous for HUMARA. Sixty-four (90.1%) patients had the same X chromosome inactivated in different tumors. Seven (9.9%) cases had different inactivated X chromosomes between multifocal tumors, indicating that those tumors were from separate progenitor cells. Five (7.0%) cases showed identical histologic features but had different inactivated HUMARA alleles. According to these results, 2 separate tumors might be synchronous primary tumors, although their histopathologic characteristics are similar. Furthermore, multifocal tumors can be of different origins despite being closely located to each other. These findings suggest that separate grouping of multiple breast tumors based on their clonal origin is needed for future studies.