Among the chromosomal regions commonly undergoing deletions in breast tumors is 11q23.1. The genes that are targets for loss of heterozygosity (LOH) in 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 increased risk of cancer, in particular breast cancer, although this is still controversial. A common assumption has been that the target for the LOH at 11q23.1 in breast carcinoma is the ATM gene, but the area studied has been too large, the density of markers too low, and the number of tumors studied has been too small to draw any firm conclusions. The present study is a multicenter study including 918 breast cancer patients with clinical information and survival data available for most of them. Primary breast tumors were investigated for LOH using a high density of microsatellite markers spanning 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 between 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(C11.2-2.8, P = 0.010) and 2.1 (C11.4-3.0, P = 0.0004) for markers D11S2179 and D11S1818, respectively. One or more of these markers are therefore most likely to be located close to or within genes associated with breast cancer survival.
Among the chromosomal regions commonly undergoing deletions in breast tumors is 11q23.1. The genes that are targets for loss of heterozygosity (LOH) in 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 increased risk of cancer, in particular breast cancer, although this is still controversial. A common assumption has been that the target for the LOH at 11q23.1 in breast carcinoma is the ATM gene, but the area studied has been too large, the density of markers too low, and the number of tumors studied has been too small to draw any firm conclusions. The present study is a multicenter study including 918 breast cancer patients with clinical information and survival data available for most of them. Primary breast tumors were investigated for LOH using a high density of microsatellite markers spanning 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 between 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 (CI 1.2–2.8, P = 0.010) and 2.1 (CI 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 close to or within genes associated with breast cancer survival. Genes Chromosomes Cancer 25:212–221, 1999. © 1999 Wiley‐Liss, Inc.
Genetic alterations of chromosome 17 have been reported to occur frequently both in human sporadic and familial malignancies. The present study was undertaken to explore the possible involvement of chromosome 17 genes including TP53 and the breast cancer susceptibility sarcoma. Fifteen patients were screened by polymerase chain reaction (PCR) for loss of heterozygosity (LOH) using four highly polymorphic markers. Loss of heterozygosity at the TP53 locus was detected in 40% (6/15) of informative cases while it was 14% (2/14) at the locus of thyroid hormone receptor alpha (THRA1), 21% (3/14) at the D17S855 locus intragenic to BRCA1 and 27% (4/15) at the D17S579 locus. In 53% of the cases studied at least one locus on chromosome 17 was affected by LOH. In our panel, the overall LOH frequency on 17p and 17q was observed to be 40% (6/15) and 27% (4/15), respectively. Comparison of LOH frequencies with clinical and prognostic features revealed significant correlation only with tumor recurrence. Our results confirm that the role of the TP53 tumor suppressor gene is important in the pathogenesis of sporadic osteosarcoma and suggest that 17q12-21 region abnormalities may be involved in the development and/or progression of this tumor.
Loss of heterozygosity (LOH) for a specific chromosome region may indicate the presence of a tumour suppressor gene (TSG). Studies on tumour LOH have therefore been helpful to identify many TSGs (Bièche and Lidereau, 1995). High incidences of LOH of the 11q22-qter chromosome region have been seen in breast cancer (Hampton et al, 1994;Gudmundsson et al, 1995;Winqvist et al, 1995;Kerangueven et al, 1997;Laake et al, 1997) and also in several other human malignancies (Herbst et al, 1995;Rasio et al, 1995;Gabra et al, 1996;Hui et al, 1996). In addition, it has been shown that chromosome 11 can suppress tumorigenicity when transferred to breast cancer (Negrini et al, 1994;Phillips et al, 1996) and melanoma cell lines (Robertson et al, 1996).The distal half of chromosome 11q contains several genes indicated to be involved in tumorigenesis; e.g. ATM (the ataxia telangiectasia disorder gene at 11q23.1), DDX10 (a putative RNA helicase gene at 11q23.1), MLL1 (a gene at 11q23 frequently rearranged in acute leukaemia), LOH11CR2A (a potential tumour suppressor gene at 11q23) and CHEK1 (a gene at 11q24 encoding a protein kinase required for the DNA damage checkpoint function) (Ziemin-van der Poel et al, 1991;Savitsky et al, 1995Savitsky et al, , 1996Furnari et al, 1997;Monaco et al, 1997;Sanchez et al, 1997).LOH at 11q23 has been reported in association with poor postmetastatic survival in breast cancer (Winqvist et al, 1995). The crucial region of LOH seemed to map between loci D11S35 (11q22) and APOC3 (apolipoprotein C-3 at 11q23) (Hampton et al, 1994), in a chromosomal segment of less than 17 Mb (Arai et al, 1996). In the initial study of a Finnish breast cancer cohort, APOC3 appeared to be the most suitable marker for more careful examinations of the clinical effects of LOH of the 11q23 chromosomal region. Therefore, in the present European multicentrestudy, we analysed tumour and normal tissue pairs of 766 primary breast cancer patients from 11 countries to investigate the association between LOH at the APOC3 locus and clinical variables in greater detail. MATERIALS AND METHODSAltogether 766 primary tumour and normal tissue pairs from breast cancer patients were collected for the LOH analysis. The Summary High frequencies of loss of heterozygosity (LOH) in chromosome 11q22-qter have been observed in various malignancies, including breast cancer. Previous studies on breast carcinomas by Winqvist et al (Cancer Res 55: 2660-2664) have indicated that a survival factor gene is located in band 11q23, and that the highly informative microsatellite polymorphism at the APOC3 locus would be a suitable tool to perform more extensive LOH studies. In this European multicentre study, we have examined the occurrence of APOC3 LOH and evaluated the effect of LOH of this chromosomal subregion on the clinical behaviour of the disease in a cohort of 766 breast cancer patients in more detail. LOH for APOC3 was found in 42% of the studied tumours, but it was not found to be significantly associated with any of the studied clinical variables,...
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