Loss of markers linked to BRCA1 precedes loss at important cell cycle regulatory genes in epithelial ovarian cancer

Advanced-stage epithelial ovarian cancers (EOC) from 114 patients were asse ssed for loss of heterozygosity (LOH or allelic imbalance) at several tumor suppressor gene loci as an initial step in identifying gene alterations im portant to the development of these tumors. The highest frequency of loss, 84% (86 of 102 cases), was observed for markers mapping near or within BRCA 1; other significant frequencies of LOH were observed for loci mapping near or within CDKN2A/CDKN2B (56%), BRCA2 (61%), RB1 (67%), or TP53 (73%). No i nstance of TP53 LOH was observed without simultaneous allelic imbalance at the BRCA1 region (P = 0.0005). LOH of CDKN2 without loss near the BRCA1 reg ion was seen in only 2 of 75 cases (P < 0.0001), and RB1 LOH without BRCA1 loss occurred in only 1 of 35 tumors (P = 0.0703). These data suggest that LOH of BRCA1, or a closely linked locus, precedes the loss of CDKN2, TP53, and RB1, and imply that inactivation of a tumor suppressor gene in this reg ion is an important early step in the development of these tumors. Genes Ch romosomes Cancer 25:65-69, 1999. (C) 1999 Wiley-Liss, Inc.