Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism

Koufos, Alex; Hansen, Marc F.; Copeland, Neal G.; Jenkins, Nancy A.; Lampkin, Beatrice C.; Cavenee, Webster K.

doi:10.1038/316330a0

Cited by 497 publications

(178 citation statements)

References 26 publications

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“…At the endogenous tk locus little difference was seen between the two types of mutants, complete loss of the functional allele being common. Data from a mouse lymphoma cell line suggest that multilocus lesions are less likely to be lethal at the heterozygous tk locus than at the hemizygous hprt locus (Evans et al, 1986), and analyses of the aprt locus in rodent cells as well as studies of certain human tumours support the notion that complex genetic events play a role in expression of recessive mutations at heterozygous loci (Koufos et al, 1985;Cavanee, 1986). On the other hand, the finding that ionizing radiation but not mitomycin-C-induced mutations at the tk locus showed similar genetic changes to those of spontaneous mutants is reminiscent of the findings at the aprt locus, and could be interpreted that a similar molecular process is involved in the generation of either mutant.…”

mentioning

confidence: 80%

Ionizing radiation-induced mutagenesis

Breimer

1988

Br J Cancer

148

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mentioning

confidence: 80%

Ionizing radiation-induced mutagenesis

Breimer

1988

Br J Cancer

148

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“…Wilms; tumour, Beckwith-Weidemann syndrome (Ping et al, 1989), adrenocortical carcinoma, rhabdomyosarcoma (Koufos et al, 1985) and mammary carcinoma (Ali et al, 1987) allele loss at llpl5.5 is frequently detected with allele specific polymorphisms in the insulin gene, and these losses are not always associated with detectable changes in the more proximal region of the short arm. (Haselbacher et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

Tumour suppression associated with expression of human insulin-like growth factor II

Schofield

Lee²,

Hill³

et al. 1991

Br J Cancer

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Recent circumstantial evidence has implicated Insulin-like growth factor II in the genesis of several tumour types, notably developmental tumours (Scott et al., 1985; Schofield & Tate, 1987; Wilkins et al., 1989). This type of tumour, thought to originate during the defective differentiation of organ precursors (Miereau et al., 1987), often expresses greatly elevated levels of mRNA for IGF-II, a known mitogen for these cells and abundantly expressed in their presumed normal counterparts (Scott et al., 1985; Schofield & Tate, 1987; Gray et al., 1987). It has been proposed that continued, inappropriate expression of this gene drives tumour growth by an autocrine mechanism. In order to examine the potential role of IGF-II in the growth of tumour cells an IGF-II cDNA was introduced into a retroviral expression vector, and used to infect a cloned fibroblast cell line. Expression of IGF-II conferred a degree of serum independence of growth in cell culture, however, when cells were injected into nude mice as subcutaneous grafts, clones expressing IGF-II from the retrovirus were found to have a greatly increased (five fold) latency of sarcoma formation. After a prolonged lag all cell lines eventually gave rise to tumours in which the introduced IGF-II genes had either been lost or inactivated, suggesting that in this system IGF-II acts as a tumour suppressor gene. Images Figure 2 Figure 4

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“…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. 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.…”

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

Chen

Shen

Karnik

2004

Intl Journal of Cancer

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Allelic loss at the short arm of chromosome 11 is one of the most common and potent events in the progression and metastasis of breast cancer. Here, we present evidence that the Integrin-Linked Kinase (ILK) gene maps to the commonly deleted chromosome 11p15. Genetic alterations that occur in breast cancer are believed to be of importance for initiation as well as progression of the disease. These genetic alterations lead to the loss or activation of a number of critical genes, such as those involved in cell proliferation, differentiation, apoptosis and genetic stability. The genetic abnormalities most frequently observed in breast tumors are amplification of proto-oncogenes (MYC, ERBB2 and CCND1), mutations of TP53 and loss of heterozygosity (LOH) on chromosomes 3p, 6q, 7q, 8p, 9p, 11, 13q, 17, 18q and 22q. 1,2 Metastatic phenotypes have been linked to such genes as NME1 (17q), CDH1 (16q), BRMS1 (11q) and KISS1 (1q). 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. 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. Although considerable advances have been made in the fine-mapping of chromosome 11p15.5, the tumor/metastasis suppressor gene(s) encoded by this region has evaded identification.Integrin-linked kinase (ILK) is an intriguing serine/threonine kinase that has been implicated in integrin-, growth-factor-and Wnt-signaling pathways. 18 It binds to the cytoplasmic domains of ␤1 and ␤3 integrins and mediates the downstream signaling events in integrin function. 19 Interactions between integrins and their ligands are involved in the regulation of many cellular functions, including embryonic development, cell proliferation, tumor growth and the ability to metastasize. 20 In Drosophila, the absence of ILK function causes defects similar to loss of integrin adhesion, and ILK mutations cause embryonic lethality and defects in muscle attachment. 21 Although ILK maps to the commonly deleted chromosome 11p, the potential of this gene in tumor/metastasis suppression has not been evaluated. We have therefore analyzed the effect of ILK expression on the in vitro and in vivo tumor growth and invasion of human mammary carcinoma cells. MATERIAL AND METHODS Mapping of ILK to LOH region 2Two YAC clones (847a12 and 696H10), a BAC clone (BAC 1760) and a PAC clone (PAC1331) overlapped the LOH region 2 and were used to...

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Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism

Cited by 497 publications

References 26 publications

Ionizing radiation-induced mutagenesis

Ionizing radiation-induced mutagenesis

Tumour suppression associated with expression of human insulin-like growth factor II

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

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