GENETIC PROGRESSION, HISTOLOGICAL GRADE, AND ALLELIC LOSS IN DUCTAL CARCINOMA IN-SITU OF THE BREAST

To investigate the relationships of specific allelic losses to progres sion and histological grade of ductal carcinoma in situ (DCIS) of the breast, we studied PCR-amplified microsatellite markers on ten chromos omal arms in 41 cases of DCIS without synchronous invasive cancer. For all chromosomal arms combined, the number of allelic losses was signi ficantly greater in lesions of intermediate or high nuclear grade (5.6 chromosomal arms/case) than in lesions of low nuclear grade (1.2 chro mosomal arms/ case). Allelic losses of 16q and 17p were commonly found in low nuclear grade DCIS (38 and 34%, respectively) as well as in in termediate and high nuclear grade DCIS (58 and 95%, respectively). All elic losses of other chromosomal arms examined (1p, 1q, 6q, 9p, 11p, 1 1q, 13q, and 17q) were uncommonly seen in low-grade DCIS, but were see n at frequencies of greater than 40% in intermediate- and high-grade D CIS. In 10 of the cases (24%), we identified patterns of allelic loss heterogeneity suggestive of intralesional progression, findings that w ere possible because multiple tumor foci from each lesion were individ ually microdissected and studied. For these tumors with allelic loss h eterogeneity, we reasoned that chromosomal losses common to all tumor foci most likely preceded the chromosomal losses observed only in tumo r foci of a more advanced genetic stage. In 9 of these 10 cases, all t umor 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-gra de DCIS. Tumors of intermediate and high nuclear grade usually have al lelic losses of significantly more chromosomal arms, often including 1 p, 1q, 6q, 9p, 11p, 11q, 13q, and 17q. Allelic loss of these chromosom al arms may occur later in DCIS progression.