Multiple regions of chromosome 6q affected by loss of heterozygosity in primary human breast carcinomas

Abstract

Summary A total of 80 primary human breast carcinoma DNAs were analysed for loss of heterozygosity (LOH) on the long arm of chromosome 6, using microsatellite markers whose location has been defined physically and by linkage analysis. Loss of heterozygosity was observed in 38 of 80 (48%) tumours that were informative for at least one locus. The analysis revealed partial or interstitial deletions of chromosome 6q. Detailed mapping of chromosome 6q in these tumour DNAs identified two and perhaps three commonly deleted regions. One of these is located between markers D6S251 and D6S252 (6q14 -q16.2), another between D6S268 and D6S261 (6q 16.3 -q23) and a third between D6S287 and D6S270 (6q22.3 -q23. 1).Keywords: breast cancer; deletion; chromsome 6q; tumour-suppressor gene Cytogenetic (Dutrillaux et al., 1990;Lu et al., 1993;Thompson et al., 1993; Trent et al., 1985Trent et al., , 1993 and molecular analyses (reviewed in Callahan et al., 1993) of primary human breast carcinomas have documented frequently occurring genetic alterations that take place during the evolution of tumour development. It is thought that these mutations either inactivate normal growth controls or give the tumour some selective advantage. At the molecular level, loss of heterozygosity (LOH) is the most frequent type of genetic alteration in primary human breast tumours . LOH at specific chromosomal loci has been taken as evidence for the presence of putative tumour-suppressor genes within the affected regions (Knudson, 1989). In sporadic primary human breast carcinomas LOH has been detected on at least 12 different chromosome arms . However only in the case of chromosome l7pl3 has the target gene for LOH (TP53) been identified (Hollstein et al., 1991). Generally one allele of the target gene is lost and the remaining allele contains a nonsense or missense mutation. The involvement of chromosome 6q in breast carcinomas has been noted in cytogenetic analysis of primary tumours (Dutrillaux et al., 1990;Lu et al., 1993;Thompson et al., 1993; Trent et al., 1985Trent et al., , 1993. Similarly, molecular analysis of primary breast tumour DNAs has shown that chromosome 6q is frequently affected by LOH (Devilee et al., 1991). In this report, we describe studies aimed at defining the location of putative tumour-suppressor gene(s) on Table I. The PCR products were diluted with loading buffer (95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol), heat denatured and rapidly cooled. Samples were run in pairs (tumour and lymphocyte PCR product from the same patient) on a denaturing gel (7% acrylamide, 32% formamide, 6 M urea, 1 x TBE) at a constant 30-35 W. After electrophoresis the gel was transferred to 3MM Whatman paper and autoradiography performed with Kodak X-Omat AR film at -70'C. When the signal of an allele in tumour DNA was less than 50% of intensity observed in matching normal DNA from a heterozygous patient, LOH was considered to have occurred (Bieche et al., 1993). ResultsPreliminary results obtained at 6 loci (D6S254,...

Parkin , a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27

“…Chromosomal region 6q25-q27 has frequently undergone deletions in a wide spectrum of human neoplasms, such as melanoma, ovarian cancer, breast cancer, non-Hodgkin's B cell lymphoma, and several others (9,10,13,17,19). Because of the recent availability of the human genome draft sequence, we were able to construct a 3.5-Mb bacterial artificial chromosome͞P1 bacteriophage artificial chromosome-derived contig encompassing the D6S1581 and D6S1008 interval at human chromosome 6q25-q27 (Fig.…”

Suppression of tumorigenicity in human ovarian cancer cell lines is controlled by a 2 cM fragment in chromosomal region 6q24-q25

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PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes

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