Comparative genomic hybridization of breast tumors stratified by histological grade reveals new insights into the biological progression of breast cancer

How does breast cancer progress? There is evidence both to support (S, W, D uffy et al,, Br, J, Cancer, 64: 1133-1138, 1991; R, Rajakariar et al., Br, J, Cancer, 71: 150-154, 1995) and refute (M, Hakama et nl., Lancet, 345: 22 1-224, 1995; R. R, R Millis et al, fur. J. Cancer, 34 548-553, 1998) the hy pothesis of dedifferentiation; the theory that as breast cancers grow they evolve from well differentiated (grade I) to poorly differentiated (grade I II) tumors, We provide evidence to support the view that the majority of gr ade I tumors do not progress to grade III tumors. Comparative genomic hybri dization was used to screen entire genomes of a large sample (40 grade I an d 50 grade III) of invasive ductal breast carcinomas, stratified by grade, We found distinct genetic differences between grade I and grade III tumors. Significantly, we found that 65% of grade I tumors lost the long arm of ch romosome 16 compared with only 16% of grade III tumors. This pattern of los s leads us to conclude that the majority of grade I tumors do not progress to grade III tumors. These findings have important implications because the y suggest that different breast tumor grades may have distinct molecular or igins, pathogenesis, and behavior and, therefore, potentially present disti nct molecular targets for research and treatment.