Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis

Abstract

Chromosome 11p15 has attracted considerable attention because of the biological importance of this region to human disease. Apart from being an important tumor suppressor locus showing loss of heterozygosity (LOH) in several adult and childhood cancers, 11p15 has been shown by linkage analysis to harbor the gene(s) for the Beckwith-Wiedemann syndrome. Furthermore, the clustering of known imprinted genes in the 11p15.5 region suggests that the target gene may also be imprinted. However, positional cloning efforts to identify the target genes have been complicated by the large size (approximately 10 Mb) and complexity of LOH at 11p15. Here, we have analyzed 94 matched normal and breast tumor samples using 17 polymorphic markers that map to 11p15.5-15.4. We have defined precisely the location of a breast tumor suppressor gene between the markers D11S1318 and D11S4088 (approximately 500 kb) within 11p15.5. LOH at this region occurred in approximately 35-45% of breast tumors analyzed. In addition, we have fine-mapped a second, critical region of LOH, that spans the markers D11S1338-D11S1323 (approximately 336 kb) at 11p15.5-p15.4, that is lost in approximately 55-60% of breast tumors. There is a striking correlation between the loss of the two 11p loci and the clinical and histopathological features of breast tumors. LOH at region 1 correlated significantly (P = 0.016) with early events in malignancy and invasiveness. In contrast, the loss of the more proximal region 2, is highly predictive (P = 0.012) of aggressive metastatic disease. Thus, two distinct tumor suppressor loci on chromosome 11p15 may contribute to tumor progression and metastasis in breast cancer. The fine mapping of this intriguing chromosomal region should facilitate the cloning of the target genes and provide critical clues to understanding the mechanisms that contribute to the evolution of adult and childhood cancers.

Suppression of malignant growth of human breast cancer cells by ectopic expression of integrin‐linked kinase

“…1). 6 We constructed a 500 kb genomic contig (data not shown) that includes the critical region between D11S1760 and D11S1331. Using a PCR-based screening method, we initially isolated PAC and BAC clones that contained D11S1760 and D11S1331 markers.…”

“…1,3-5 LOH analyses have defined regions of deletion associated with metastasis on chromosomes 3p21, 15q14, 16q22 and 11p15. 2,6 Frequent genetic alterations on chromosome 11p15 suggest a crucial role for this region in breast 6,7 and other adult 8 -12 and childhood cancers. [13][14][15][16][17] More recently, we have mapped 2 distinct regions on chromosome 11p15.5 that are subject to LOH during breast tumor progression and metastasis.…”

“…[13][14][15][16][17] More recently, we have mapped 2 distinct regions on chromosome 11p15.5 that are subject to LOH during breast tumor progression and metastasis. 6 LOH at region 1 correlated with tumors that contain ductal carcinoma in situ, suggesting that the loss of a critical gene in this region may be responsible for early events in malignancy. LOH at region 2 correlated with a more aggressive tumor and an ominous outlook for the patient, such as aneuploidy, high S-phase fraction and the presence of metastasis in regional lymph nodes.…”

Impairment of MLH1 and CDKN2A in oncogenesis of laryngeal cancer

“…Sizes and quantity of marker alleles were evaluated by a semiautomated analysis using GENESCAN software, version 3.1, and the GENOTYPER software package, version 2.0 (Applied Biosystems, USA). Allelic loss was defined as a more than 70% reduction in the tumour peak area compared to the peak area of corresponding normal tissue (Karnik et al, 1998). PCR with methylation-specific primers (MSP-PCR) was used to assess the promoter methylation of the CDKN2A.…”

Decreased expression of haemoglobin beta (HBB) gene in anaplastic thyroid cancer and recovory of its expression inhibits cell growth

“…In addition, there were several reports of LOH in various kinds of cancers at this locus. In this region, there were two distinct tumour-suppressor loci that implicated breast cancer progression and metastasis (Karnik et al, 1998). It is suggested that an LOH of 11p15.5 might relate to poor prognosis of nonsmall-cell lung cancer (Bepler et al, 2002).…”