Loss of heterozygosity at 11q23.1 and survival in breast cancer: Results of a large European study

Among the chromosomal regions commonly undergoing deletions in breast tumor s is 11q23.1. The genes that are targets for loss of heterozygosity (LOH) i n this region is not yet established. One of the candidate genes located in this region is ATM, responsible for the rare autosomal recessive disorder ataxia-telangiectasia (A-T). Interestingly, A-T heterozygotes may have an i ncreased risk of cancer, in particular breast cancer, although this is stil l controversial. A common assumption has been that the target for the LOH a t 11q23.1 in breast carcinoma is the ATM gene, but the area studied has bee n too large, the density of markers too low, and the number of tumors studi ed has been too small to draw any firm conclusions. The present study is a multicenter study including 918 breast cancer patients with clinical inform ation and survival data available for most of them. Primary breast tumors w ere investigated for LOH using a high density of microsatellite markers spa nning approximately 6 Mb around the ATM gene. Survival analyses showed that there are most likely one or more candidate genes in a 3-4 Mb region betwe en the markers D11S1819 and D11S927 including the ATM gene. Cancer-specific survival was significantly reduced in patients whose tumors exhibited LOH of markers D11S2179 (within the ATM gene), D11S1778, D11S1294, and D11S1818 . The highest survival hazard ratios were 1.8 (Cl 1.2-2.8, P = 0.010) and 2 .1 (Cl 1.4-3.0, P = 0.0004) for markers D11S2179 and D11S1818, respectively . One or more of these markers are therefore most likely to be located clos e to or within genes associated with breast cancer survival. (C) 1999 Wiley -Liss, Inc.