Molecular changes in primary breast tumors and the Nottingham Histologic Score

Pathological grade is routinely used to stratify breast cancer patients into favorable and less favorable outcome groups. Mechanisms by which genomic changes in breast tumors specifically contribute to the underlying components of tumor grade - tubule formation, nuclear pleomorphism, and mitoses - are unknown. This study examined 26 chromosomal regions known to be altered in breast cancer in 256 invasive breast carcinomas. Differences in overall levels and patterns of allelic imbalance (AI) at each chromosomal region were compared for tumors with favorable (=1) and unfavorable (=3) scores for tubule formation, nuclear pleomorphism and mitotic count. Levels of AI were significantly different between samples with high and low scores for tubule formation (P < 0.001), nuclear pleomorphism (P < 0.001) and mitotic count (P < 0.05). Significantly higher levels of AI were detected at regions 11q23 and 13q12 for tumors with reduced tubule formation, chromosomes 9p21, 11q23, 13q14, 17p13 and 17q12 for those with high levels of nuclear atypia, and chromosomes 1p36, 11q23, and 13q14 for those with high mitotic counts. Region 16q11-q22 showed significantly more AI events in samples with low nuclear atypia. Patterns of genetic changes associated with poorly-differentiated breast tumors were recapitulated by the individual components of the Nottingham Histologic Score. While frequent alteration of 11q23 is common for reduced tubule formation, high nuclear atypia and high mitotic counts, suggesting that this is an early genetic change in the development of poorly-differentiated breast tumors, alterations at the other seven loci associated with poorly-differentiated tumors may specifically influence cell structure, nuclear morphology and cellular proliferation.