17q21-q25 aberrations in breast cancer: combined allelotyping and CGH analysis reveals 5 regions of allelic imbalance among which two correspond to DNA amplification.
Chromosome 17q is frequently rearranged in breast cancer. Allelotyping studies have proposed the existence of at least four regions of allelic imbalance (AI). Here we present a study combining allelotyping using 19 CA repeat markers mapping in the 17q21-25 region and molecular cytogenetics (CGH and FISH). Allelotyping was undertaken on 178 pairs of cognate tumor and normal DNA in order to determine the number of regions of AI and define the shortest overlaps. AI ranged from 34-54% of the informative cases according to the marker and, overall, 66% of the tumors presented AI at one of the markers tested. Analysis of the patterns of imbalances revealed at least five common regions of imbalance respectively defined by markers: D17S855, which is intragenic of BRCA1 (SRO 1), D17S1607 (SRO 2), D17S1855 (SRO 3), between D17S789 and D17S785 (SRO 4) and D17S784 (SRO 5). In order to characterize the nature of the genetic events revealed by allelotyping we performed CGH analysis on a subset of 43 tumors presenting variable patterns of imbalance. CGH showed that AI at 17q could represent four different types of genetic events: loss of chromosome 17, gain of 17q, gain of 17q22-q24, loss of 17q11-q21 and/or 17q25-qter. Some of these anomalies could occur concomitantly within the same tumor. Since 35% of the tumors analysed by CGH presented gains, these data indicated that AI at 17q were not solely indicative of losses of genetic material and could also represent DNA amplification. Gains were most commonly observed in the 17q23-q24 regions. This suggested that AI in SRO 2 and SRO 3 corresponded to DNA amplification. To assess this, we isolated BAC clones by PCR screening for markers D17S1607 and D17S1855 and used these in FISH experiments on six breast tumor cell lines and 14 breast cancer specimens. FISH results showed that both D17S1607 and D17S1855 were frequently involved in DNA amplification (8-30 copies). Altogether, our data show that allelotyping can be efficiently used in amplicon mapping. Clinico-pathological correlations indicated that imbalance at 17q preferentially occurred in high grade, PR- and ERBB2 amplified tumors.
Orsetti
B
B
Equipe Génome et Cancer, UMR 5535 CNRS, Centre de Recherche CRLC Val d'Aurelle-Paul Lamarque, Montpellier, France.
Courjal
F
F
Cuny
M
M
Rodriguez
C
C
Theillet
C
C
D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics*; D018275:Carcinoma, Lobular / Q000235:genetics*; D002869:Chromosome Aberrations; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009006:Monosomy; D009693:Nucleic Acid Hybridization
D004273:DNA, Neoplasm