Invasive Tubular Carcinoma of the Breast Frequently is Clonally Related to Flat Epithelial Atypia and Low-grade Ductal Carcinoma In Situ

Abstract

Low-grade precursor lesions, such flat epithelial atypia (FEA), low-grade ductal carcinoma in situ (lg-DCIS), and lobular neoplasia (LN) often coexist with invasive tubular carcinomas (TCs) of the breast. To evaluate a possible clonal relationship, we have examined a series of 27 TC and the surrounding putative precursor lesions using loss of heterozygosity analysis and mitochondrial DNA sequencing. In these lesions (22 FEA, 10 lg-DCIS, 3 LN), loss of heterozygosity was most frequently observed on the long arm of chromosome 16 as well as at chromosome 8p21, 3p14, 1p36 and 11q14 with a high degree of homology of allelic losses between FEA, lg-DCIS and tubular carcinomas. In the adjacent invasive tubular carcinomas, mitochondrial DNA sequencing revealed identical mutation patterns in 50% of the lg-DCIS and in 12 of 21 (57%) informative cases of FEA. No direct association was seen between TC and LN or columnar cell lesions without nuclear atypia. Our data indicate, that in the majority of cases lg-DCIS and FEA are directly related to tubular breast cancer with a possible precursor role.