Genetic Progression, Histological Grade, and Allelic Loss in Ductal Carcinoma in Situ of the Breast

Abstract

To investigate the relationships of specific allelic losses to progression and histological grade of ductal carcinoma in situ (DCIS) of the breast, we studied PCR-amplified microsatellite markers on ten chromosomal arms in 41 cases of DCIS without synchronous invasive cancer. For all chromosomal arms combined, the number of allelic losses was significantly greater in lesions of intermediate or high nuclear grade (5.6 chromosomal arms/case) than in lesions of low nuclear grade (1.2 chromosomal arms/case). Allelic losses of 16q and 17p were commonly found in low nuclear grade DCIS (38 and 34%, respectively) as well as in intermediate and high nuclear grade DCIS (58 and 95%, respectively). Allelic losses of other chromosomal arms examined (1p, 1q, 6q, 9p, 11p, 11q, 13q, and 17q) were uncommonly seen in low-grade DCIS, but were seen at frequencies of greater than 40% in intermediate- and high-grade DCIS. In 10 of the cases (24%), we identified patterns of allelic loss heterogeneity suggestive of intralesional progression, findings that were possible because multiple tumor foci from each lesion were individually microdissected and studied. For these tumors with allelic loss heterogeneity, we reasoned that chromosomal losses common to all tumor foci most likely preceded the chromosomal losses observed only in tumor foci of a more advanced genetic stage. In 9 of these 10 cases, all tumor foci lost 16q, and in 8 of the 10 cases, all tumor foci lost 17p. Together, these observations indicate that chromosomal losses of 16q and 17p occur early in DCIS progression and are common even in low-grade DCIS. Tumors of intermediate and high nuclear grade usually have allelic losses of significantly more chromosomal arms, often including 1p, 1q, 6q, 9p, 11p, 11q, 13q, and 17q. Allelic loss of these chromosomal arms may occur later in DCIS progression.