Chromosome region 8p11-p21: refined mapping and molecular alterations in breast cancer.

Several genes, most of them unknown, of the short arm of chromosome 8 are involved in malignant diseases. Numerous studies have implicated a portion of the 8p11-p21 region as the location of one or more tumor suppressor genes involved in a variety of human cancers, including breast cancer. We and others have reported linkage analyses suggesting the presence of a putative breast cancer susceptibility gene. Furthermore, several oncogenes of the 8p11-p12 region are involved in reciprocal translocations in myeloproliferative and myelodysplastic disorders and in amplification in breast cancer. To facilitate the analysis of the 8p11-p21 region and the cloning of candidate oncogenes and tumor suppressor genes, a high-resolution physical and transcriptional map was established with 39 yeast artificial chromosomes and 94 markers, including so-called sequence-tagged sites and expressed sequence-tagged sites derived from either known genes or expressed sequence tags corresponding to unidentified transcripts. In addition, four novel transcripts were identified and localized precisely within the map. This transcription map provides a detailed description of gene order for the 8p11-p21 region and will be helpful in the identification of candidate genes for diseases. From this basis, we refined the mapping of two types of molecular alterations that occur at 8p11-p21 in sporadic breast cancers, i.e., amplification and deletion.

Loss of heterozygosity at loci from chromosome arm 22Q in human sporadic breast carcinomas.

Forty-four breast carcinomas were studied for loss of heterozygosity (LOH) at 25 microsatellite markers distributed almost evenly along chromosome arm 22q. LOH at at least one marker were observed in 66% tumors, while 6 regions of consistent LOH were identified. The size of each region ranged between 3 and 6 cM, and the distance between each region was estimated to be 8 to 12 cM. Even if not all these regions contain a bona fide tumor-suppressor gene, it is possible that several loci from chromosome arm 22q may be involved in breast carcinogenesis.

Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions.

To appreciate the involvement of known or potential susceptibility genes in sporadic breast tumors, we have searched for chromosomal deletions by studying loss of heterozygosity (LOH) at 43 microsatellite (CA)n markers from human chromosomes 10, 11 and 17, in 115 unselected consecutive samples of breast carcinoma with particular emphasis on specific regions. No site of consistent LOH was identified on chromosome 10. Five regions of LOH were contained within bands q22-24 of chromosome 11 for which nearly 50% of the tumors had LOH at at least one marker. This region is thus a major site of deletion in breast cancer and several tumor suppressor genes seem to be involved. One of them may be the ataxia telangiectasia (ATM) gene which is located in one of the affected regions. Five regions of LOH, one of which is within the BRCA1 gene area, were recognized along chromosome 17. LOH at three of these regions were found in highly proliferative tumors. When combined with a previous study of chromosome 13 with emphasis on BRCA2 and Rb1 genes, this work allowed to distinguish a total of 12 regions of LOH, variably affected in breast tumors and correlated with prognostic parameters.

Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas.

Deletions of genomic regions involving tumor suppressor genes are thought to be important in the initiation and progression of breast cancer. We conducted a genome-wide search for deleted regions in a series of 75 human breast carcinomas by studying the allelic patterns of 184 microsatellite markers distributed over all chromosomes and looking for loss of heterozygosity (LOH). We identified 56 regions of consistent LOH. Strikingly, every tumor had a different set of deletions. To study this complexity, we applied a phylogenetic-like type of analysis. Each region was involved in a certain proportion of tumors, ranging from 20 to 62%; the most frequently involved regions were on chromosome arms 8p, 11q, 16q, and 17p. There was a correlation (P = 0.005) between the level of LOH and the size of the tumors. Tumors with a high level of LOH were also highly proliferative and had a high mitotic index.

Cumulative regional allelotyping of human breast carcinomas.

We have analyzed losses of heterozygosity (LOH) at markers from chromosomes 1, 2, 4 and 5 in a panel of 53 consecutive breast carcinomas. Together with a parallel analysis of LOH at chromosome 3, this allowed the identification of twenty-one regions of LOH. In contrast, in a comparative analysis of chromosome X, no region of loss could be defined. Cumulative regional allelotyping of 38 tumors with 71 markers from the five autosomes (37% of the genome) enabled the study of the respective distribution of regions of frequent loss, to identify associations of regions of LOH, and to distinguish tumors frequently affected by LOH such as lobular carcinomas.

Multiple sites of loss of heterozygosity on chromosome arms 3p and 3q in human breast carcinomas.

Loss of heterozygosity (LOH) at loci from both arms of chromosome 3 were shown to occur in a high proportion of breast carcinomas. Six regions of consistent loss were identified, and were variably involved in the tumors. This suggests that multiple potential tumor suppressor genes involved in mammary carcinogenesis are present on chromosome 3.

Patterns of loss of heterozygosity at loci from chromosome arm 13q suggests a possible involvement of BRCA2 in sporadic breast tumors.

Loss of heterozygosity (LOH) at loci from chromosome 13 is frequently observed in breast cancer. Chromosome 13 contains at least two cancer genes, the well-characterized RB1 gene located at 13q14 and the breast cancer-susceptibility gene, BRCA2, recently localized to 13q12. To investigate the possible involvement of BRCA2 in sporadic breast tumors, we looked at LOH at eight microsatellite (CA)n markers distributed along chromosome 13 in a panel of 59 primary breast carcinomas. We show that some LOH does not include the RB1 locus and is associated with the BRCA2 gene region.

Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8.

We have analysed losses of heterozygosity (LOH) at eight markers from the p12-p22 region of human chromosome 8 in a panel of 113 breast tumors. LOH were detected in almost half of the tumors. The most frequently deleted region included microsatellite (CA)n repeats markers D8S258, D8S133 and D8S259, located at 8p12-p22, while markers NEFL and LPL appeared less frequently altered. In parallel, linkage analysis was performed using the same informative markers, to test for the involvement of chromosome 8p loci in familial breast cancer. Positive cumulative multipoint lod score of 2.51 at theta = 0.0 was obtained with markers NEFL and D8S259. These results suggest that region 8p12-p22 carries at least one tumor suppressor gene involved in sporadic and perhaps also in familial breast cancer.