Pathological and biological relevance of cytophotometric DNA content to breast carcinoma genetic progression

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Abstract
Correlating cytophotometrically detectable genetic alterations to events of known biological and pathological significance in breast carcinoma has been challenging, in large part owing to the difficulty in isolating and analyzing premalignant (i.e., hyperplastic) or preinvasive (i.e., in situ carcinoma) lesions. This problem may be addressed by using histologically directed evaluation of intact, paraffin‐embedded tissue sections. Using image cytophotometry in preserved sections, we have identified clonal DNA content abnormalities (i.e., aneuploidy) in up to three‐fourths of preinvasive breast carcinomas. Moreover, comparison of ploidy determinations between residual in situ and corresponding invading neoplastic populations suggests that host invasion is accompanied by measurable DNA content shifts in many cases. Image cytophotometric DNA content abnormalities are also detectable in florid/atypical proliferative lesions, albeit less frequently (∼25% of cases) and to a lesser extent (i.e., near‐diploid) than in situ carcinomas. Taken together, these findings imply an association between clonal DNA content aberrations and histologic disease progression. Although the sensitivity of cytophotometric ploidy assessments in tissue sections is limited by nuclear sectioning artifact and overlap, the presence of genomic instability in precursor lesions is supported by evidence of individual chromosome aneuploidy, which can be demonstrated in tissue sections by interphase cytogenetics with fluorescent, centromere‐specific probes. Further, presence of intra‐tumoral clonal DNA content heterogeneity is confirmed by cytogenetic studies showing co‐existing near‐diploid chromosome number modes in many tumors with hyperdiploid stemlines. Karyotypic stemline analyses imply polyploidization events are an important mechanism of clonal evolution leading to genetic heterogeneity. Recent studies also demonstrate predictable relationships between cytophotometric and karyotypic alterations, as well as between cytophotometric ploidy and molecular level events. Therefore, we conclude that cytophotometrically detectable DNA content anomalies may precede unequivocal morphologic transformation in breast neoplasia. Moreover, clonal DNA content evolution via endoreduplication may not only accompany biologically critical steps in histologic progression of breast tumors, but may also be reflected in DNA histogram patterns.